Journal articles: 'Flightless protein'

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Davy, D. A., H. D. Campbell, S. Fountain, D. de Jong, and M. F. Crouch. "The flightless I protein colocalizes with actin- and microtubule-based structures in motile Swiss 3T3 fibroblasts: evidence for the involvement of PI 3-kinase and Ras-related small GTPases." Journal of Cell Science 114, no. 3 (February 1, 2001): 549–62. http://dx.doi.org/10.1242/jcs.114.3.549.

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The flightless I protein contains an actin-binding domain with homology to the gelsolin family and is likely to be involved in actin cytoskeletal rearrangements. It has been suggested that this protein is involved in linking the cytoskeletal network with signal transduction pathways. We have developed antibodies directed toward the leucine rich repeat and gelsolin-like domains of the human and mouse homologues of flightless I that specifically recognize expressed and endogenous forms of the protein. We have also constructed a flightless I-enhanced green fluorescent fusion vector and used this to examine the localization of the expressed protein in Swiss 3T3 fibroblasts. The flightless I protein localizes predominantly to the nucleus and translocates to the cytoplasm following serum stimulation. In cells stimulated to migrate, the flightless I protein colocalizes with beta-tubulin- and actin-based structures. Members of the small GTPase family, also implicated in cytoskeletal control, were found to colocalize with flightless I in migrating Swiss 3T3 fibroblasts. LY294002, a specific inhibitor of PI 3-kinase, inhibits the translocation of flightless I to actin-based structures. Our results suggest that PI 3-kinase and the small GTPases, Ras, RhoA and Cdc42 may be part of a common functional pathway involved in Fliih-mediated cytoskeletal regulation. Functionally, we suggest that flightless I may act to prepare actin filaments or provide factors required for cytoskeletal rearrangements necessary for cell migration and/or adhesion.

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de Couet, H. G., K. S. Fong, A. G. Weeds, P. J. McLaughlin, and G. L. Miklos. "Molecular and mutational analysis of a gelsolin-family member encoded by the flightless I gene of Drosophila melanogaster." Genetics 141, no. 3 (November 1, 1995): 1049–59. http://dx.doi.org/10.1093/genetics/141.3.1049.

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Abstract The flightless locus of Drosophila melanogaster has been analyzed at the genetic, molecular, ultrastructural and comparative crystallographic levels. The gene encodes a single transcript encoding a protein consisting of a leucine-rich amino terminal half and a carboxyterminal half with high sequence similarity to gelsolin. We determined the genomic sequence of the flightless landscape, the breakpoints of four chromosomal rearrangements, and the molecular lesions in two lethal and two viable alleles of the gene. The two alleles that lead to flight muscle abnormalities encode mutant proteins exhibiting amino acid replacements within the S1-like domain of their gelsolin-like region. Furthermore, the deduced intron-exon structure of the D. melanogaster gene has been compared with that of the Caenorhabditis elegans homologue. Furthermore, the sequence similarities of the flightless protein with gelsolin allow it to be evaluated in the context of the published crystallographic structure of the S1 domain of gelsolin. Amino acids considered essential for the structural integrity of the core are found to be highly conserved in the predicted flightless protein. Some of the residues considered essential for actin and calcium binding in gelsolin S1 and villin V1 are also well conserved. These data are discussed in light of the phenotypic characteristics of the mutants and the putative functions of the protein.

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Campbell, H. D., T. Schimansky, C. Claudianos, N. Ozsarac, A. B. Kasprzak, J. N. Cotsell, I. G. Young, H. G. de Couet, and G. L. Miklos. "The Drosophila melanogaster flightless-I gene involved in gastrulation and muscle degeneration encodes gelsolin-like and leucine-rich repeat domains and is conserved in Caenorhabditis elegans and humans." Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11386–90. http://dx.doi.org/10.1073/pnas.90.23.11386.

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Mutations at the flightless-I locus (fliI) of Drosophila melanogaster cause flightlessness or, when severe, incomplete cellularization during early embryogenesis, with subsequent abnormalities in mesoderm invagination and in gastrulation. After chromosome walking, deficiency mapping, and transgenic analysis, we have isolated and characterized flightless-I cDNAs, enabling prediction of the complete amino acid sequence of the 1256-residue protein. Data base searches revealed a homologous gene in Caenorhabditis elegans, and we have isolated and characterized corresponding cDNAs. By using the polymerase chain reaction with nested sets of degenerate oligonucleotide primers based on conserved regions of the C. elegans and D. melanogaster proteins, we have cloned a homologous human cDNA. The predicted C. elegans and human proteins are, respectively, 49% and 58% identical to the D. melanogaster protein. The predicted proteins have significant sequence similarity to the actin-binding protein gelsolin and related proteins and, in addition, have an N-terminal domain consisting of a repetitive amphipathic leucine-rich motif. This repeat is found in D. melanogaster, Saccharomyces cerevisiae, and mammalian proteins known to be involved in cell adhesion and in binding to other proteins. The structure of the maternally expressed flightless-I protein suggests that it may play a key role in embryonic cellularization by interacting with both the cytoskeleton and other cellular components. The presence of a highly conserved homologue in nematodes, flies, and humans is indicative of a fundamental role for this protein in many metazoans.

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Carpentier, Samuel J., Minjian Ni, Jeffrey M. Duggan, Richard G. James, Brad T. Cookson, and Jessica A. Hamerman. "The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1." Science Signaling 12, no. 581 (May 14, 2019): eaau0615. http://dx.doi.org/10.1126/scisignal.aau0615.

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B cell adaptor for phosphoinositide 3-kinase (PI3K) (BCAP) is a signaling adaptor that activates the PI3K pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2. Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1β release from macrophages. Accordingly, caspase-1–dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro–caspase-1 within the NLRP3/ASC preinflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages.

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Takimoto, Masato. "Multidisciplinary Roles of LRRFIP1/GCF2 in Human Biological Systems and Diseases." Cells 8, no. 2 (January 31, 2019): 108. http://dx.doi.org/10.3390/cells8020108.

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Leucine Rich Repeat of Flightless-1 Interacting Protein 1/GC-binding factor 2 (LRRFIP1/GCF2) cDNA was cloned for a transcriptional repressor GCF2, which bound sequence-specifically to a GC-rich element of epidermal growth factor receptor (EGFR) gene and repressed its promotor. LRRFIP1/GCF2 was also cloned as a double stranded RNA (dsRNA)-binding protein to trans-activation responsive region (TAR) RNA of Human Immunodeficiency Virus-1 (HIV-1), termed as TAR RNA interacting protein (TRIP), and as a binding protein to the Leucine Rich Repeat (LRR) of Flightless-1(Fli-1), termed as Flightless-1 LRR associated protein 1 (FLAP1) and LRR domain of Flightless-1 interacting Protein 1 (LRRFIP1). Subsequent functional studies have revealed that LRRFIP1/GCF2 played multiple roles in the regulation of diverse biological systems and processes, such as in immune response to microorganisms and auto-immunity, remodeling of cytoskeletal system, signal transduction pathways, and transcriptional regulations of genes. Dysregulations of LRRFIP1/GCF2 have been implicated in the causes of several experimental and clinico-pathological states and the responses to them, such as autoimmune diseases, excitotoxicity after stroke, thrombosis formation, inflammation and obesity, the wound healing process, and in cancers. LRRFIP1/GCF2 is a bioregulator in multidisciplinary systems of the human body and its dysregulation can cause diverse human diseases.

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O’Rourke, Allison R., and Jessica A. Hamerman. "Flightless-1 promotes lung CD103+ cDC phagocytosis and migration." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.14. http://dx.doi.org/10.4049/jimmunol.204.supp.69.14.

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Abstract Dendritic cells are specialized antigen-presenting cells integral for bridging the innate and adaptive immune responses. Critical to dendritic cell function is the need for a dynamic actin cytoskeleton. Flightless-1 is an actin capping protein linked to processes vital for dendritic cell immune functions including cell extension formation, phagocytosis, cell migration, and cell adhesion. Consistent with an important role in actin dynamics, whole body Flightless-1 knockouts are embryonic lethal. To enable further study of Flightless-1 in the immune response, we made mice with dendritic cell Flightless-1 deficiency using the CD11c-CRE driver. Homeostatic cDC1 and cDC2 populations in the spleen and lymph nodes were unchanged in DC-Flightless-1 knockouts relative to control animals. However, DC-Flightless-1 ablation led to a developmental disadvantage when in competition with WT DCs in mixed bone marrow chimeras. Upon LPS challenge in the airways, the Flightless-deficient cDC1 population showed reduced phagocytosis and migration to the lung draining lymph nodes. The DC migratory defect in the absence of Flightless-1 was supported by decreased CCR7 expression in both cDC1 and cDC2 populations. We hypothesize that the observed defects in phagocytosis and migration in Flightless-1-deficient dendritic cells are due to an altered actin cytoskeleton, which may also affect other actin-based immune structures. Current experiments are testing this hypothesis, and investigating the ability of Flightless-deficient DC to prime T cell responses.

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Navarro-Payá, David, Ilona Flis, Michelle A. E. Anderson, Philippa Hawes, Ming Li, Omar S. Akbari, Sanjay Basu, and Luke Alphey. "Targeting female flight for genetic control of mosquitoes." PLOS Neglected Tropical Diseases 14, no. 12 (December 3, 2020): e0008876. http://dx.doi.org/10.1371/journal.pntd.0008876.

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Aedes aegypti Act4 is a paralog of the Drosophila melanogaster indirect flight muscle actin gene Act88F. Act88F has been shown to be haploinsufficient for flight in both males and females (amorphic mutants are dominant). Whereas Act88F is expressed in indirect flight muscles of both males and females, expression of Act4 is substantially female-specific. We therefore used CRISPR/Cas9 and homology directed repair to examine the phenotype of Act4 mutants in two Culicine mosquitoes, Aedes aegypti and Culex quinquefasciatus. A screen for dominant female-flightless mutants in Cx. quinquefasciatus identified one such mutant associated with a six base pair deletion in the CxAct4 coding region. A similar screen in Ae. aegypti identified no dominant mutants. Disruption of the AeAct4 gene by homology-dependent insertion of a fluorescent protein marker cassette gave a recessive female-flightless phenotype in Ae. aegypti. Reproducing the six-base deletion from Cx. quinquefasciatus in Ae. aegypti using oligo-directed mutagenesis generated dominant female-flightless mutants and identified additional dominant female-flightless mutants with other in-frame insertions or deletions. Our data indicate that loss of function mutations in the AeAct4 gene are recessive but that short in-frame deletions produce dominant-negative versions of the AeAct4 protein that interfere with flight muscle function. This makes Act4 an interesting candidate for genetic control methods, particularly population-suppression gene drives targeting female viability/fertility.

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Straub, K. L., M. C. Stella, and M. Leptin. "The gelsolin-related flightless I protein is required for actin distribution during cellularisation in Drosophila." Journal of Cell Science 109, no. 1 (January 1, 1996): 263–70. http://dx.doi.org/10.1242/jcs.109.1.263.

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We have analysed the developmental defects in Drosophila embryos lacking a gelsolin-related protein encoded by the gene flightless I. Such embryos have previously been reported to gastrulate abnormally. We now show that the most dramatic defects are seen earlier, in actin-dependent events during cellularisation of the syncytial blastoderm, a process with similarities to cytokinesis. The blastoderm nuclei migrate to the periphery of the egg normally but lose their precise cortical positioning during cellularisation. Cleavage membranes are initially formed, but invaginate irregularly and often fail to close at the basal end of the newly formed cells. The association of actin with the cellularisation membranes is irregular, suggesting a role for flightless I in the delivery of actin to the actin network, or in its stabilisation.

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Arora, P. D., K. Nakajima, A. Nanda, A. Plaha, A. Wilde, D. B. Sacks, and C. A. McCulloch. "Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling." Molecular Biology of the Cell 31, no. 15 (July 15, 2020): 1595–610. http://dx.doi.org/10.1091/mbc.e19-10-0554.

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10

Lee, Young-Ho, Hugh D. Campbell, and Michael R. Stallcup. "Developmentally Essential Protein Flightless I Is a Nuclear Receptor Coactivator with Actin Binding Activity." Molecular and Cellular Biology 24, no. 5 (March 1, 2004): 2103–17. http://dx.doi.org/10.1128/mcb.24.5.2103-2117.2004.

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ABSTRACT Hormone-activated nuclear receptors (NR) activate transcription by recruiting multiple coactivator complexes to the promoters of target genes. One important coactivator complex includes a p160 coactivator (e.g., GRIP1, SRC-1, or ACTR) that binds directly to activated NR, the histone acetyltransferase p300 or CBP, and the arginine-specific histone methyltransferase CARM1. We previously demonstrated that the coactivator function of CARM1 depends both on the methyltransferase activity and on additional unknown proteins that bind to CARM1. In this study a yeast two-hybrid screen for proteins that bind CARM1 identified the protein Flightless I (Fli-I), which has essential roles in Drosophila and mouse development. Fli-I bound to CARM1, GRIP1, and NRs and cooperated synergistically with CARM1 and GRIP1 to enhance NR function. Fli-I bound poorly to and did not cooperate with PRMT1, a CARM1-related protein arginine methyltransferase that also functions as an NR coactivator. The synergy between GRIP1, CARM1, and Fli-I required the methyltransferase activity of CARM1. The C-terminal AD1 (binding site for p300/CBP) and AD2 (binding site for CARM1) activation domains of GRIP1 contributed to the synergy but were less stringently required than the N-terminal region of GRIP1, which is the binding site for Fli-I. Endogenous Fli-I was recruited to the estrogen-regulated pS2 gene promoter of MCF-7 cells in response to the hormone, and reduction of endogenous Fli-I levels by small interfering RNA reduced hormone-stimulated gene expression by the endogenous estrogen receptor. A fragment of Fli-I that is related to the actin binding protein gelsolin enhanced estrogen receptor activity, and mutations that reduced actin binding also reduced the coactivator function of this Fli-I fragment. These data suggest that Fli-I may facilitate interaction of the p160 coactivator complex with other coactivators or coactivator complexes containing actin or actin-like proteins.

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Chen, Anan, Pam D. Arora, Christine C. Lai, John W. Copeland, Trevor F. Moraes, Christopher A. McCulloch, Brigitte D. Lavoie, and Andrew Wilde. "The scaffold-protein IQGAP1 enhances and spatially restricts the actin-nucleating activity of Diaphanous-related formin 1 (DIAPH1)." Journal of Biological Chemistry 295, no. 10 (January 31, 2020): 3134–47. http://dx.doi.org/10.1074/jbc.ra119.010476.

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The actin cytoskeleton is a dynamic array of filaments that undergoes rapid remodeling to drive many cellular processes. An essential feature of filament remodeling is the spatio-temporal regulation of actin filament nucleation. One family of actin filament nucleators, the Diaphanous-related formins, is activated by the binding of small G-proteins such as RhoA. However, RhoA only partially activates formins, suggesting that additional factors are required to fully activate the formin. Here we identify one such factor, IQ motif containing GTPase activating protein-1 (IQGAP1), which enhances RhoA-mediated activation of the Diaphanous-related formin (DIAPH1) and targets DIAPH1 to the plasma membrane. We find that the inhibitory intramolecular interaction within DIAPH1 is disrupted by the sequential binding of RhoA and IQGAP1. Binding of RhoA and IQGAP1 robustly stimulates DIAPH1-mediated actin filament nucleation in vitro. In contrast, the actin capping protein Flightless-I, in conjunction with RhoA, only weakly stimulates DIAPH1 activity. IQGAP1, but not Flightless-I, is required to recruit DIAPH1 to the plasma membrane where actin filaments are generated. These results indicate that IQGAP1 enhances RhoA-mediated activation of DIAPH1 in vivo. Collectively these data support a model where the combined action of RhoA and an enhancer ensures the spatio-temporal regulation of actin nucleation to stimulate robust and localized actin filament production in vivo.

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Archer, S. K., C. A. Behm, C. Claudianos, and H. D. Campbell. "The Flightless I protein and the gelsolin family in nuclear hormone receptor-mediated signalling." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 940–42. http://dx.doi.org/10.1042/bst0320940.

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The Drosophila melanogaster flightless I protein and its homologues in higher eukaryotes (FliI) are conserved members of the gelsolin family of actin-binding proteins. Members of the gelsolin family generally contain three or six copies of a 125-amino-acid residue gelsolin-related repeating unit, and may contain additional domains including the C-terminal villin-related ‘headpiece’ or N-terminal extensions such as the leucine-rich repeat of the FliI protein. Numerous studies including work done with mouse knockouts for gelsolin, villin and CapG support a role for the family in cytoskeletal actin dynamics. In both fruitfly and mouse, the FliI protein is also essential for early development. Recent studies indicate that supervillin, gelsolin and FliI are involved in intracellular signalling via nuclear hormone receptors including the androgen, oestrogen and thyroid hormone receptors. This unexpected role in signalling has opened a new area in research on the gelsolin family and is providing important new insights into the mechanisms of gene regulation via nuclear receptors.

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Cripps, R. M., E. Ball, M. Stark, A. Lawn, and J. C. Sparrow. "Recovery of dominant, autosomal flightless mutants of Drosophila melanogaster and identification of a new gene required for normal muscle structure and function." Genetics 137, no. 1 (May 1, 1994): 151–64. http://dx.doi.org/10.1093/genetics/137.1.151.

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Abstract To identify further mutations affecting muscle function and development in Drosophila melanogaster we recovered 22 autosomal dominant flightless mutations. From these we have isolated eight viable and lethal alleles of the muscle myosin heavy chain gene, and seven viable alleles of the indirect flight muscle (IFM)-specific Act88F actin gene. The Mhc mutations display a variety of phenotypic effects, ranging from reductions in myosin heavy chain content in the indirect flight muscles only, to reductions in the levels of this protein in other muscles. The Act88F mutations range from those which produce no stable actin and have severely abnormal myofibrillar structure, to those which accumulate apparently normal levels of actin in the flight muscles but which still have abnormal myofibrils and fly very poorly. We also recovered two recessive flightless mutants on the third chromosome. The remaining five dominant flightless mutations are all lethal alleles of a gene named lethal(3)Laker. The Laker alleles have been characterized and the gene located in polytene bands 62A10,B1-62B2,4. Laker is a previously unidentified locus which is haplo-insufficient for flight. In addition, adult wild-type heterozygotes and the lethal larval trans-heterozygotes show abnormalities of muscle structure indicating that the Laker gene product is an important component of muscle.

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Vaziri, Pooneh, Danielle Ryan, Christopher A. Johnston, and Richard M. Cripps. "A Novel Mechanism for Activation of Myosin Regulatory Light Chain by Protein Kinase C-Delta in Drosophila." Genetics 216, no. 1 (August 4, 2020): 177–90. http://dx.doi.org/10.1534/genetics.120.303540.

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Myosin is an essential motor protein, which in muscle is comprised of two molecules each of myosin heavy-chain (MHC), the essential or alkali myosin light-chain 1 (MLC1), and the regulatory myosin light-chain 2 (MLC2). It has been shown previously that MLC2 phosphorylation at two canonical serine residues is essential for proper flight muscle function in Drosophila; however, MLC2 is also phosphorylated at additional residues for which the mechanism and functional significance is not known. We found that a hypomorphic allele of Pkcδ causes a flightless phenotype; therefore, we hypothesized that PKCδ phosphorylates MLC2. We rescued flight disability by duplication of the wild-type Pkcδ gene. Moreover, MLC2 is hypophosphorylated in Pkcδ mutant flies, but it is phosphorylated in rescued animals. Myosin isolated from Pkcδ mutant flies shows a reduced actin-activated ATPase activity, and MLC2 in these myosin preparations can be phosphorylated directly by recombinant human PKCδ. The flightless phenotype is characterized by a shortened and disorganized sarcomere phenotype that becomes apparent following eclosion. We conclude that MLC2 is a direct target of phosphorylation by PKCδ, and that this modification is necessary for flight muscle maturation and function.

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Davy, Deborah A., Eldon E. Ball, Klaus I. Matthaei, Hugh D. Campbell, and Michael F. Crouch. "The flightless I protein localizes to actin‐based structures during embryonic development." Immunology & Cell Biology 78, no. 4 (August 2000): 423–29. http://dx.doi.org/10.1046/j.1440-1711.2000.00926.x.

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Warmke, J., M. Yamakawa, J. Molloy, S. Falkenthal, and D. Maughan. "Myosin light chain-2 mutation affects flight, wing beat frequency, and indirect flight muscle contraction kinetics in Drosophila." Journal of Cell Biology 119, no. 6 (December 15, 1992): 1523–39. http://dx.doi.org/10.1083/jcb.119.6.1523.

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We have used a combination of classical genetic, molecular genetic, histological, biochemical, and biophysical techniques to identify and characterize a null mutation of the myosin light chain-2 (MLC-2) locus of Drosophila melanogaster. Mlc2E38 is a null mutation of the MLC-2 gene resulting from a nonsense mutation at the tenth codon position. Mlc2E38 confers dominant flightless behavior that is associated with reduced wing beat frequency. Mlc2E38 heterozygotes exhibit a 50% reduction of MLC-2 mRNA concentration in adult thoracic musculature, which results in a commensurate reduction of MLC-2 protein in the indirect flight muscles. Indirect flight muscle myofibrils from Mlc2E38 heterozygotes are aberrant, exhibiting myofilaments in disarray at the periphery. Calcium-activated Triton X-100-treated single fiber segments exhibit slower contraction kinetics than wild type. Introduction of a transformed copy of the wild type MLC-2 gene rescues the dominant flightless behavior of Mlc2E38 heterozygotes. Wing beat frequency and single fiber contraction kinetics of a representative rescued line are not significantly different from those of wild type. Together, these results indicate that wild type MLC-2 stoichiometry is required for normal indirect flight muscle assembly and function. Furthermore, these results suggest that the reduced wing beat frequency and possibly the flightless behavior conferred by Mlc2E38 is due in part to slower contraction kinetics of sarcomeric regions devoid or partly deficient in MLC-2.

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Mohammad, Ibrahim, Pamma D. Arora, Yeganeh Naghibzadeh, Yongqiang Wang, Jeff Li, Wendall Mascarenhas, Paul A. Janmey, John F. Dawson, and Christopher A. McCulloch. "Flightless I is a focal adhesion‐associated actin‐capping protein that regulates cell migration." FASEB Journal 26, no. 8 (May 11, 2012): 3260–72. http://dx.doi.org/10.1096/fj.11-202051.

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Kopecki, Z., and A. J. Cowin. "Flightless I: An actin-remodelling protein and an important negative regulator of wound repair." International Journal of Biochemistry & Cell Biology 40, no. 8 (2008): 1415–19. http://dx.doi.org/10.1016/j.biocel.2007.04.011.

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Idelfonso-García, Osiris Germán, Brisa Rodope Alarcón-Sánchez, Verónica Rocío Vásquez-Garzón, Rafael Baltiérrez-Hoyos, Saúl Villa-Treviño, Pablo Muriel, Héctor Serrano, Julio Isael Pérez-Carreón, and Jaime Arellanes-Robledo. "Is Nucleoredoxin a Master Regulator of Cellular Redox Homeostasis? Its Implication in Different Pathologies." Antioxidants 11, no. 4 (March 30, 2022): 670. http://dx.doi.org/10.3390/antiox11040670.

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Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer’s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies.

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Yang, Gink N., Xanthe L. Strudwick, Claudine S. Bonder, Zlatko Kopecki, and Allison J. Cowin. "Increased Expression of Flightless I in Cutaneous Squamous Cell Carcinoma Affects Wnt/β-Catenin Signaling Pathway." International Journal of Molecular Sciences 22, no. 24 (December 8, 2021): 13203. http://dx.doi.org/10.3390/ijms222413203.

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Cutaneous squamous cell carcinoma (cSCC) accounts for 25% of cutaneous malignancies diagnosed in Caucasian populations. Surgical removal in combination with radiation and chemotherapy are effective treatments for cSCC. Nevertheless, the aggressive metastatic forms of cSCC still have a relatively poor patient outcome. Studies have linked actin cytoskeletal dynamics and the Wnt/β-catenin signaling pathway as important modulators of cSCC pathogenesis. Previous studies have also shown that the actin-remodeling protein Flightless (Flii) is a negative regulator of cSCC. The aim of this study was to investigate if the functional effects of Flii on cSCC involve the Wnt/β-catenin signaling pathway. Flii knockdown was performed using siRNA in a human late stage aggressive metastatic cSCC cell line (MET-1) alongside analysis of Flii genetic murine models of 3-methylcholanthrene induced cSCC. Flii was increased in a MET-1 cSCC cell line and reducing Flii expression led to fewer PCNA positive cells and a concomitant reduction in cellular proliferation and symmetrical division. Knockdown of Flii led to decreased β-catenin and a decrease in the expression of the downstream effector of β-catenin signaling protein SOX9. 3-Methylcholanthrene (MCA)-induced cSCC in Flii overexpressing mice showed increased markers of cancer metastasis including talin and keratin-14 and a significant increase in SOX9 alongside a reduction in Flii associated protein (Flap-1). Taken together, this study demonstrates a role for Flii in regulating proteins involved in cSCC proliferation and tumor progression and suggests a potential role for Flii in aggressive metastatic cSCC.

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Campbell, Hugh D., Shelley Fountain, Ian S. McLennan, Leise A. Berven, Michael F. Crouch, Deborah A. Davy, Jane A. Hooper, et al. "Fliih, a Gelsolin-Related Cytoskeletal Regulator Essential for Early Mammalian Embryonic Development." Molecular and Cellular Biology 22, no. 10 (May 15, 2002): 3518–26. http://dx.doi.org/10.1128/mcb.22.10.3518-3526.2002.

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ABSTRACT The Drosophila melanogaster flightless I gene is required for normal cellularization of the syncytial blastoderm. Highly conserved homologues of flightless I are present in Caenorhabditis elegans, mouse, and human. We have disrupted the mouse homologue Fliih by homologous recombination in embryonic stem cells. Heterozygous Fliih mutant mice develop normally, although the level of Fliih protein is reduced. Cultured homozygous Fliih mutant blastocysts hatch, attach, and form an outgrowing trophoblast cell layer, but egg cylinder formation fails and the embryos degenerate. Similarly, Fliih mutant embryos initiate implantation in vivo but then rapidly degenerate. We have constructed a transgenic mouse carrying the complete human FLII gene and shown that the FLII transgene is capable of rescuing the embryonic lethality of the homozygous targeted Fliih mutation. These results confirm the specific inactivation of the Fliih gene and establish that the human FLII gene and its gene product are functional in the mouse. The Fliih mouse mutant phenotype is much more severe than in the case of the related gelsolin family members gelsolin, villin, and CapG, where the homozygous mutant mice are viable and fertile but display alterations in cytoskeletal actin regulation.

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Sackton, Timothy B., Phil Grayson, Alison Cloutier, Zhirui Hu, Jun S. Liu, Nicole E. Wheeler, Paul P. Gardner, et al. "Convergent regulatory evolution and loss of flight in paleognathous birds." Science 364, no. 6435 (April 4, 2019): 74–78. http://dx.doi.org/10.1126/science.aat7244.

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A core question in evolutionary biology is whether convergent phenotypic evolution is driven by convergent molecular changes in proteins or regulatory regions. We combined phylogenomic, developmental, and epigenomic analysis of 11 new genomes of paleognathous birds, including an extinct moa, to show that convergent evolution of regulatory regions, more so than protein-coding genes, is prevalent among developmental pathways associated with independent losses of flight. A Bayesian analysis of 284,001 conserved noncoding elements, 60,665 of which are corroborated as enhancers by open chromatin states during development, identified 2355 independent accelerations along lineages of flightless paleognaths, with functional consequences for driving gene expression in the developing forelimb. Our results suggest that the genomic landscape associated with morphological convergence in ratites has a substantial shared regulatory component.

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Arora, P. D., T. He, K. Ng, and C. A. McCulloch. "The leucine-rich region of Flightless I interacts with R-ras to regulate cell extension formation." Molecular Biology of the Cell 29, no. 20 (October 2018): 2481–93. http://dx.doi.org/10.1091/mbc.e18-03-0147.

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Flightless I (FliI) is a calcium-dependent, actin severing and capping protein that localizes to cell matrix adhesions, contributes to the generation of cell extensions, and colocalizes with Ras. Currently, the mechanism by which FliI interacts with Ras to enable assembly of actin-based cell protrusions is not defined. R-Ras, but not K-ras, H-ras, or N-ras, associated with the leucine-rich region (LRR) of FliI. Mutations of the proline-rich region of R-ras (P202A, P203A) prevented this association. Knockdown of Ras GTPase-activating SH3 domain-binding protein (G3BP1) or Rasgap120 by small interfering RNA inhibited the formation of cell extensions and prevented interaction of R-ras and G3BP1 in FliI wild-type (WT) cells. Pull-down assays using G3BP1 fusion proteins showed a strong association of R-ras with the C-terminus of G3BP1 (amino acids 236–466), which also required the LRR of FliI. In cells that expressed the truncated N-terminus or C-terminus of G3BP1, the formation of cell extensions was blocked. Endogenous Rasgap120 interacted with the N-terminus of G3BP1 (amino acids 1–230). We conclude that in cells plated on collagen FliI-LRR interacts with R-ras to promote cell extension formation and that FliI is required for the interaction of Rasgap120 with G3BP1 to regulate R-ras activity and growth of cell extensions.

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Goodall, Alison H., Philippa Burns, Isabelle Salles, Iain C. Macaulay, Chris I. Jones, Diego Ardissino, Bernard de Bono, et al. "Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function." Blood 116, no. 22 (November 25, 2010): 4646–56. http://dx.doi.org/10.1182/blood-2010-04-280925.

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Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.

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Quong, A. A., M. Gormley, R. Meng, V. B. Bhat, and A. L. Rosenberg. "Low abundance protein enrichment for discovery of plasma protein biomarkers for early detection of breast cancer." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 77. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.77.

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77 Background: Protein biomarkers for breast cancer are desired for early diagnosis, disease prognosis and drug response monitoring. Biomarkers in bodily fluids, such as plasma, allow for non-invasive monitoring and have additional value compared to tissue-based markers. Plasma-based biomarker discovery faces a challenge in that the wide dynamic range of protein concentrations prevents the detection of lower abundance proteins. In this study, we have investigated the use of a novel protein enrichment strategy combined with isobaric label-based LC-MS/MS as well as two experimental designs for the identification of biomarkers of early stage breast cancer. Methods: Plasma from 12 patients with benign breast lesions and 12 with stage I breast cancer were processed using ProteoMiner enrichment followed by on-bead digestion. Two types of standards were investigated: a pooled standard, consisting of equal portions from the 24 plasma digests and a universal standard. The samples were digested, labeled and analyzed using by HPLC-Chip/Q-TOF analysis. Proteins were identified and quantified using Spectrum Mill software. Results: Use of ProteoMiner beads resulted in extraction of sufficient protein for at least 10 technical replicates and cut down preparation time by 80%, as compared to MARS-based immunodepletion. A total of 414 plasma proteins were identified, 89% of which are low abundance plasma proteins and 14 of which were differentially expressed. Expression values normalized using the pooled vs. universal standards were significantly correlated. Conclusions: This study demonstrated use of the ProteoMiner technology for enrichment of low abundance proteins from plasma. Fourteen plasma-based biomarkers of stage I breast cancer were identified with statistical significance. A number of these proteins (e.g., protocadherin FAT2, flightless-1 homolog) have been linked to breast cancer relevant processes, such as cell migration, adhesion, estrogen receptor signaling and proliferation.

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Arora, Pamma D., Yongqiang Wang, Anne Bresnick, Paul A. Janmey, and Christopher A. McCulloch. "Flightless I interacts with NMMIIA to promote cell extension formation, which enables collagen remodeling." Molecular Biology of the Cell 26, no. 12 (June 15, 2015): 2279–97. http://dx.doi.org/10.1091/mbc.e14-11-1536.

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We examined the role of the actin-capping protein flightless I (FliI) in collagen remodeling by mouse fibroblasts. FliI-overexpressing cells exhibited reduced spreading on collagen but formed elongated protrusions that stained for myosin10 and fascin and penetrated pores of collagen-coated membranes. Inhibition of Cdc42 blocked formation of cell protrusions. In FliI-knockdown cells, transfection with constitutively active Cdc42 did not enable protrusion formation. FliI-overexpressing cells displayed increased uptake and degradation of exogenous collagen and strongly compacted collagen fibrils, which was blocked by blebbistatin. Mass spectrometry analysis of FliI immunoprecipitates showed that FliI associated with nonmuscle myosin IIA (NMMIIA), which was confirmed by immunoprecipitation. GFP-FliI colocalized with NMMIIA at cell protrusions. Purified FliI containing gelsolin-like domains (GLDs) 1–6 capped actin filaments efficiently, whereas FliI GLD 2–6 did not. Binding assays showed strong interaction of purified FliI protein (GLD 1–6) with the rod domain of NMMIIA ( kD = 0.146 μM), whereas FliI GLD 2–6 showed lower binding affinity ( kD = 0.8584 μM). Cells expressing FliI GLD 2–6 exhibited fewer cell extensions, did not colocalize with NMMIIA, and showed reduced collagen uptake compared with cells expressing FliI GLD 1–6. We conclude that FliI interacts with NMMIIA to promote cell extension formation, which enables collagen remodeling in fibroblasts.

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Bagashev, Asen, Michael C. Fitzgerald, David F. LaRosa, Patrick P. Rose, Sara Cherry, Alfred C. Johnson, and Kathleen E. Sullivan. "Leucine-Rich Repeat (in Flightless I) Interacting Protein-1 Regulates a Rapid Type I Interferon Response." Journal of Interferon & Cytokine Research 30, no. 11 (November 2010): 843–52. http://dx.doi.org/10.1089/jir.2010.0017.

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Zhang, Shuang, Hui Yan, Chao-Zheng Li, Yi-Hong Chen, Feng-hua Yuan, Yong-gui Chen, Shao-Ping Weng, and Jian-Guo He. "Identification and Function of Leucine-Rich Repeat Flightless-I-Interacting Protein 2 (LRRFIP2) in Litopenaeus vannamei." PLoS ONE 8, no. 2 (February 28, 2013): e57456. http://dx.doi.org/10.1371/journal.pone.0057456.

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Deng, Su, Ruth L. Silimon, Mridula Balakrishnan, Ingo Bothe, Devin Juros, David B. Soffar, and Mary K. Baylies. "The actin polymerization factor Diaphanous and the actin severing protein Flightless I collaborate to regulate sarcomere size." Developmental Biology 469 (January 2021): 12–25. http://dx.doi.org/10.1016/j.ydbio.2020.09.014.

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Kopecki, Zlatko, Gink N. Yang, Jessica E. Jackson, Elizabeth L. Melville, Matthew P. Caley, Dedee F. Murrell, Ian A. Darby, Edel A. O’Toole, Michael S. Samuel, and Allison J. Cowin. "Cytoskeletal protein flightless I inhibits apoptosis, enhances tumor cell invasion and promotes cutaneous squamous cell carcinoma progression." Oncotarget 6, no. 34 (October 19, 2015): 36426–40. http://dx.doi.org/10.18632/oncotarget.5536.

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CHRISTAKI (Ε. ΧΡΗΣΤΑΚΗ), E. "Some principles of ostriches nutrition and their products." Journal of the Hellenic Veterinary Medical Society 52, no. 1 (January 31, 2018): 18. http://dx.doi.org/10.12681/jhvms.15402.

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The ostriches have been farmed for about 150 years in South Africa. They are flightless birds but fast runners. Adults usually weigh more than 130 kg and stand up to 2.7 m tall. Domesticated ostriches reach maturity at 2-3 years old. Theirgastrointestinal tract is more similar to that of ruminants than to poultry's. The ostriches derive a lot of energy from feed fibre through the production of volatile fatty acids, in large intestine. The ostriches tend to be a credible competitor in the red meat market because of the quality of its meat (low in cholesterol and fat, high protein) .The eggs and nearly all parts, feathers, leather and meat, of the slaughtered ostrich can be used for commercial purposes.

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Wilson, S. "TRIP: a novel double stranded RNA binding protein which interacts with the leucine rich repeat of flightless I." Nucleic Acids Research 26, no. 15 (August 1, 1998): 3460–67. http://dx.doi.org/10.1093/nar/26.15.3460.

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Austin, Jane E., and Leigh H. Fredrickson. "Body and Organ Mass and Body Composition of Postbreeding Female Lesser Scaup." Auk 104, no. 4 (October 1, 1987): 694–99. http://dx.doi.org/10.1093/auk/104.4.694.

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Abstract Changes in body and organ mass and body composition of postbreeding female Lesser Scaup (Aythya affinis) were investigated in the prairie-pothole region of southwestern Manitoba. Body mass was lowest during the wing molt and peaked during the migratory period. Most digestive organs gradually increased in mass through the postbreeding season. Lipid reserves remained relatively constant from the preflightless through the postflightless periods (x̄ = 43 g). The marked increase in lipids in the migratory period (x̄ = 183 g, P < 0.05) corresponded with premigratory hyperphagia. Time spent feeding explained 87% of the variation in lipid levels during the postbreeding season. Protein reserves declined with the onset of wing molt (P < 0.001) and increased during the postflightless period (P < 0.05). Breast muscle mass followed a similar pattern and was strongly correlated with molt intensity (r = 0.799, P < 0.001). Protein reserves, in particular the breast muscles, provide at least part of the protein required for feather production. Low body mass and lipid reserves during molt may not indicate energetic or nutritional stress but, alternatively, may be part of a postbreeding strategy to minimize energy demands and to reduce the length of the flightless period.

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Cho, Il Kyu, Chiou Ling Chang, and Qing X. Li. "Diet-Induced Over-Expression of Flightless-I Protein and Its Relation to Flightlessness in Mediterranean Fruit Fly, Ceratitis capitata." PLoS ONE 8, no. 12 (December 3, 2013): e81099. http://dx.doi.org/10.1371/journal.pone.0081099.

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Ruzehaji, Nadira, Stuart J. Mills, Elizabeth Melville, Ruth Arkell, Robert Fitridge, and Allison J. Cowin. "The Influence of Flightless I on Toll-Like-Receptor-Mediated Inflammation in a Murine Model of Diabetic Wound Healing." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/389792.

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Impaired wound healing and ulceration represent a serious complication of both type 1 and type 2 diabetes. Cytoskeletal protein Flightless I (Flii) is an important inhibitor of wound repair, and reduced Flii gene expression in fibroblasts increased migration, proliferation, and adhesion. As such it has the ability to influence all phases of wound healing including inflammation, remodelling and angiogenesis. Flii has the potential to modulate inflammation through its interaction with MyD88 which it an adaptor protein for TLR4. To assess the effect of Flii on the inflammatory response of diabetic wounds, we used a murine model of streptozocin-induced diabetes and Flii genetic mice. Increased levels of Flii were detected in Flii transgenic murine wounds resulting in impaired healing which was exacerbated when diabetes was induced. When Flii levels were reduced in diabetic wounds of Flii-deficient mice, healing was improved and decreased levels of TLR4 were observed. In contrast, increasing the level of Flii in diabetic mouse wounds led to increased TLR4 and NF-κB production. Treatment of murine diabetic wounds with neutralising antibodies to Flii led to an improvement in healing with decreased expression of TLR4. Decreasing the level of Flii in diabetic wounds may therefore reduce the inflammatory response and improve healing.

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Wang, Cuihua, Kezhi Chen, Shengyou Liao, Wei Gu, Xinlei Lian, Jing Zhang, Xuejuan Gao, et al. "The flightless I protein interacts with RNA-binding proteins and is involved in the genome-wide mRNA post-transcriptional regulation in lung carcinoma cells." International Journal of Oncology 51, no. 1 (May 11, 2017): 347–61. http://dx.doi.org/10.3892/ijo.2017.3995.

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Cripps, R. M., K. D. Becker, M. Mardahl, W. A. Kronert, D. Hodges, and S. I. Bernstein. "Transformation of Drosophila melanogaster with the wild-type myosin heavy-chain gene: rescue of mutant phenotypes and analysis of defects caused by overexpression." Journal of Cell Biology 126, no. 3 (August 1, 1994): 689–99. http://dx.doi.org/10.1083/jcb.126.3.689.

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We have transformed Drosophila melanogaster with a genomic construct containing the entire wild-type myosin heavy-chain gene, Mhc, together with approximately 9 kb of flanking DNA on each side. Three independent lines stably express myosin heavy-chain protein (MHC) at approximately wild-type levels. The MHC produced is functional since it rescues the mutant phenotypes of a number of different Mhc alleles: the amorphic allele Mhc1, the indirect flight muscle and jump muscle-specific amorphic allele Mhc10, and the hypomorphic allele Mhc2. We show that the Mhc2 mutation is due to the insertion of a transposable element in an intron of Mhc. Since a reduction in MHC in the indirect flight muscles alters the myosin/actin protein ratio and results in myofibrillar defects, we determined the effects of an increase in the effective copy number of Mhc. The presence of four copies of Mhc results in overabundance of the protein and a flightless phenotype. Electron microscopy reveals concomitant defects in the indirect flight muscles, with excess thick filaments at the periphery of the myofibrils. Further increases in copy number are lethal. These results demonstrate the usefulness and potential of the transgenic system to study myosin function in Drosophila. They also show that overexpression of wild-type protein in muscle may disrupt the function of not only the indirect flight but also other muscles of the organism.

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Thomas, Hannah M., Parinaz Ahangar, Benjamin R. Hofma, Xanthe L. Strudwick, Robert Fitridge, Stuart J. Mills, and Allison J. Cowin. "Attenuation of Flightless I Increases Human Pericyte Proliferation, Migration and Angiogenic Functions and Improves Healing in Murine Diabetic Wounds." International Journal of Molecular Sciences 21, no. 16 (August 5, 2020): 5599. http://dx.doi.org/10.3390/ijms21165599.

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Pericytes are peri-vascular mural cells which have an important role in the homeostatic regulation of inflammatory and angiogenic processes. Flightless I (Flii) is a cytoskeletal protein involved in regulating cellular functions, but its involvement in pericyte activities during wound healing is unknown. Exacerbated inflammation and reduced angiogenesis are hallmarks of impaired diabetic healing responses, and strategies aimed at regulating these processes are vital for improving healing outcomes. To determine the effect of altering Flii expression on pericyte function, in vitro and in vivo studies were performed to assess the effect on healing, inflammation and angiogenesis in diabetic wounds. Here, we demonstrated that human diabetic wounds display upregulated expression of the Flii protein in conjunction with a depletion in the number of platelet derived growth factor receptor β (PDGFRβ) +/ neural glial antigen 2 (NG2) + pericytes present in the dermis. Human pericytes were found to be positive for Flii and attenuating its expression in vitro through siRNA knockdown led to enhanced proliferation, migration and angiogenic functions. Genetic knockdown of Flii in a streptozotocin-induced murine model of diabetes led to increased numbers of pericytes within the wound. This was associated with dampened inflammation, an increased rate of angiogenic repair and improved wound healing. Our findings show that Flii expression directly impacts pericyte functions, including proliferation, motility and angiogenic responses. This suggests that Flii regulation of pericyte function may be in part responsible for the changes in pericyte-related processes observed in diabetic wounds.

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Liu, Yu-Tsueng, and Helen L. Yin. "Identification of the Binding Partners for Flightless I, A Novel Protein Bridging the Leucine-rich Repeat and the Gelsolin Superfamilies." Journal of Biological Chemistry 273, no. 14 (April 3, 1998): 7920–27. http://dx.doi.org/10.1074/jbc.273.14.7920.

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Liu, J., A. G. Bang, C. Kintner, A. P. Orth, S. K. Chanda, S. Ding, and P. G. Schultz. "Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis." Proceedings of the National Academy of Sciences 102, no. 6 (January 26, 2005): 1927–32. http://dx.doi.org/10.1073/pnas.0409472102.

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41

Karlik, C. C., D. L. Saville, and E. A. Fyrberg. "Two missense alleles of the Drosophila melanogaster act88F actin gene are strongly antimorphic but only weakly induce synthesis of heat shock proteins." Molecular and Cellular Biology 7, no. 9 (September 1987): 3084–91. http://dx.doi.org/10.1128/mcb.7.9.3084-3091.1987.

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We have characterized two extant mutations of the flight muscle-specific act88F actin gene of Drosophila melanogaster. Both defective alleles were recovered from flightless mutants isolated previously (K. Mogami and Y. Hotta, Mol. Gen. Genet. 183:409-417, 1981). By directly sequencing the mutant alleles, we demonstrated that in act88FIfm(3)2 a single G-C to A-T transition converted arginine-28 to cysteine and that in act88FIfm(3)4 a single A-T to T-A transversion changed isoleucine-76 to phenylalanine. We showed that the actins encoded by either allele were strongly antimorphic. Mutant alleles effectively disrupted myofibril structure and function in the flight muscles of strains having the diploid complement of wild-type act88F genes. However, unlike antimorphic actins encoded by three previously characterized act88F alleles, neither that encoded by act88FIfm(3)2 nor that encoded by act88FIfm(3)4 was a strong inducer of heat shock protein synthesis.

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Guo, Jian, Hong-Wen Tang, Jing Li, Norbert Perrimon, and Dong Yan. "Xio is a component of the Drosophila sex determination pathway and RNA N6-methyladenosine methyltransferase complex." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): 3674–79. http://dx.doi.org/10.1073/pnas.1720945115.

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N6-methyladenosine (m6A), the most abundant chemical modification in eukaryotic mRNA, has been implicated in Drosophila sex determination by modifying Sex-lethal (Sxl) pre-mRNA and facilitating its alternative splicing. Here, we identify a sex determination gene, CG7358, and rename it xio according to its loss-of-function female-to-male transformation phenotype. xio encodes a conserved ubiquitous nuclear protein of unknown function. We show that Xio colocalizes and interacts with all previously known m6A writer complex subunits (METTL3, METTL14, Fl(2)d/WTAP, Vir/KIAA1429, and Nito/Rbm15) and that loss of xio is associated with phenotypes that resemble other m6A factors, such as sexual transformations, Sxl splicing defect, held-out wings, flightless flies, and reduction of m6A levels. Thus, Xio encodes a member of the m6A methyltransferase complex involved in mRNA modification. Since its ortholog ZC3H13 (or KIAA0853) also associates with several m6A writer factors, the function of Xio in the m6A pathway is likely evolutionarily conserved.

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43

Karlik, C. C., D. L. Saville, and E. A. Fyrberg. "Two missense alleles of the Drosophila melanogaster act88F actin gene are strongly antimorphic but only weakly induce synthesis of heat shock proteins." Molecular and Cellular Biology 7, no. 9 (September 1987): 3084–91. http://dx.doi.org/10.1128/mcb.7.9.3084.

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We have characterized two extant mutations of the flight muscle-specific act88F actin gene of Drosophila melanogaster. Both defective alleles were recovered from flightless mutants isolated previously (K. Mogami and Y. Hotta, Mol. Gen. Genet. 183:409-417, 1981). By directly sequencing the mutant alleles, we demonstrated that in act88FIfm(3)2 a single G-C to A-T transition converted arginine-28 to cysteine and that in act88FIfm(3)4 a single A-T to T-A transversion changed isoleucine-76 to phenylalanine. We showed that the actins encoded by either allele were strongly antimorphic. Mutant alleles effectively disrupted myofibril structure and function in the flight muscles of strains having the diploid complement of wild-type act88F genes. However, unlike antimorphic actins encoded by three previously characterized act88F alleles, neither that encoded by act88FIfm(3)2 nor that encoded by act88FIfm(3)4 was a strong inducer of heat shock protein synthesis.

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44

Adams, Damian H., Xanthe L. Strudwick, Zlatko Kopecki, Jane A. Hooper-Jones, Klaus I. Matthaei, Hugh D. Campbell, Barry C. Powell, and Allison J. Cowin. "Gender specific effects on the actin-remodelling protein Flightless I and TGF-β1 contribute to impaired wound healing in aged skin." International Journal of Biochemistry & Cell Biology 40, no. 8 (2008): 1555–69. http://dx.doi.org/10.1016/j.biocel.2007.11.024.

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Socha, R., and J. Šula. "Differential allocation of protein resources to flight muscles and reproductive organs in the flightless wing-polymorphic bug, Pyrrhocoris apterus (L.) (Heteroptera)." Journal of Comparative Physiology B 178, no. 2 (September 28, 2007): 179–88. http://dx.doi.org/10.1007/s00360-007-0209-9.

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Dahl-Halvarsson, Martin, Montse Olive, Malgorzata Pokrzywa, Katarina Ejeskär, Ruth H. Palmer, Anne Elisabeth Uv, and Homa Tajsharghi. "Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member." Proceedings of the National Academy of Sciences 115, no. 28 (June 26, 2018): E6566—E6575. http://dx.doi.org/10.1073/pnas.1800727115.

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Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7 are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

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González-Morales, Nicanor, Thomas W. Marsh, Anja Katzemich, Océane Marescal, Yu Shu Xiao, and Frieder Schöck. "Different Evolutionary Trajectories of Two Insect-Specific Paralogous Proteins Involved in Stabilizing Muscle Myofibrils." Genetics 212, no. 3 (May 13, 2019): 743–55. http://dx.doi.org/10.1534/genetics.119.302217.

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Alp/Enigma family members have a unique PDZ domain followed by zero to four LIM domains, and are essential for myofibril assembly across all species analyzed so far. Drosophila melanogaster has three Alp/Enigma family members, Zasp52, Zasp66, and Zasp67. Ortholog search and phylogenetic tree analysis suggest that Zasp genes have a common ancestor, and that Zasp66 and Zasp67 arose by duplication in insects. While Zasp66 has a conserved domain structure across orthologs, Zasp67 domains and lengths are highly variable. In flies, Zasp67 appears to be expressed only in indirect flight muscles, where it colocalizes with Zasp52 at Z-discs. We generated a CRISPR null mutant of Zasp67, which is viable but flightless. We can rescue all phenotypes by re-expressing a Zasp67 transgene at endogenous levels. Zasp67 mutants show extended and broken Z-discs in adult flies, indicating that the protein helps stabilize the highly regular myofibrils of indirect flight muscles. In contrast, a Zasp66 CRISPR null mutant has limited viability, but only mild indirect flight muscle defects illustrating the diverging evolutionary paths these two paralogous genes have taken since they arose by duplication.

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Kopecki, Zlatko, Natalie Stevens, Gink Yang, Elizabeth Melville, and Allison Cowin. "Recombinant Leucine-Rich Repeat Flightless-Interacting Protein-1 Improves Healing of Acute Wounds through Its Effects on Proliferation Inflammation and Collagen Deposition." International Journal of Molecular Sciences 19, no. 7 (July 10, 2018): 2014. http://dx.doi.org/10.3390/ijms19072014.

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Adams, D. H., N. Ruzehaji, X. L. Strudwick, J. E. Greenwood, H. D. Campbell, R. Arkell, and A. J. Cowin. "Attenuation of Flightless I, an actin-remodelling protein, improves burn injury repair via modulation of transforming growth factor (TGF)-β1 and TGF-β3." British Journal of Dermatology 161, no. 2 (August 2009): 326–36. http://dx.doi.org/10.1111/j.1365-2133.2009.09296.x.

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Yang, Gink N., Parinaz Ahangar, Xanthe L. Strudwick, Zlatko Kopecki, and Allison J. Cowin. "Overexpression of Flii during Murine Embryonic Development Increases Symmetrical Division of Epidermal Progenitor Cells." International Journal of Molecular Sciences 22, no. 15 (July 30, 2021): 8235. http://dx.doi.org/10.3390/ijms22158235.

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Epidermal progenitor cells divide symmetrically and asymmetrically to form stratified epidermis and hair follicles during late embryonic development. Flightless I (Flii), an actin remodelling protein, is implicated in Wnt/β-cat and integrin signalling pathways that govern cell division. This study investigated the effect of altering Flii on the divisional orientation of epidermal progenitor cells (EpSCs) in the basal layer during late murine embryonic development and early adolescence. The effect of altering Flii expression on asymmetric vs. symmetric division was assessed in vitro in adult human primary keratinocytes and in vivo at late embryonic development stages (E16, E17 and E19) as well as adolescence (P21 day-old) in mice with altered Flii expression (Flii knockdown: Flii+/−, wild type: WT, transgenic Flii overexpressing: FliiTg/Tg) using Western blot and immunohistochemistry. Flii+/− embryonic skin showed increased asymmetrical cell division of EpSCs with an increase in epidermal stratification and elevated talin, activated-Itgb1 and Par3 expression. FliiTg/Tg led to increased symmetrical cell division of EpSCs with increased cell proliferation rate, an elevated epidermal SOX9, Flap1 and β-cat expression, a thinner epidermis, but increased hair follicle number and depth. Flii promotes symmetric division of epidermal progenitor cells during murine embryonic development.

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Journal articles on the topic 'Flightless protein'

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