Drosophila Fragile X Protein controls cellular proliferation by regulating cbl levels in the ovary

Epstein, Andrew M; Bauer, Christopher R.; Ho, A.; Bosco, Giovanni; Zarnescu, Daniela C.

doi:10.1016/j.ydbio.2009.03.011

Cited by 37 publications

(36 citation statements)

References 36 publications

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“…So far, the function of FMRP in the ovary has been studied in Drosophila models, where it may be involved in germ cell and oocyte specification (Costa et al 2005, Megosh et al 2006 as well as in the maintenance of germline stem cells, probably regulating the translation of specific mRNAs via the miRNA pathway (Yang et al 2007). A role in the control of germline proliferation was also demonstrated (Epstein et al 2009), thus suggesting an early stage-specific function of Fmr1 in germ cells.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a more recent study using Drosophila dFmr1 mutants demonstrated that dFmr1 is required for germline stem cell maintenance and repression of differentiation in the ovary, probably via the miRNA pathway (Yang et al 2007). Another Drosophila FXS model showed that FMRP controls germline proliferation during oogenesis by regulating the expression of casitas B-lineage lymphoma proto-oncogene (cbl) in the developing ovary (Epstein et al 2009).…”

Section: Introductionmentioning

confidence: 99%

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Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

et al. 2013

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Fragile X mental retardation protein (FMRP) belongs to a small family of RNA-binding proteins. Its absence or inactivity is responsible for fragile X syndrome, the most common cause of inherited mental retardation. Despite its ubiquitous expression, FMRP function and expression remain almost understudied in non-neuronal tissues, though previous studies on germline development during oogenesis may suggest a special function of this protein also in ovarian tissue. In addition, the well-documented association of FMR1 premutation state with fragile X-related premature ovarian insufficiency adds interest to the role of FMRP in ovarian physiology. The aim of the present work was to investigate the expression of Fmr1 mRNA and its protein, FMRP, at different stages of rat follicular development. By immunohistochemical studies we demonstrated FMRP expression in granulosa, theca and germ cells in all stages of follicular development. In addition, changes in Fmr1 expression, both at the protein and mRNA levels, were observed. FMRP levels increased upon follicular development while preantral and early antral follicles presented similar levels of Fmr1 transcripts with decreased expression in preovulatory follicles. These observations suggest that Fmr1 expression in the ovary is regulated at different and perhaps independent levels. In addition, our results show expression of at least four different isoforms of FMRP during all stages of follicular growth with expression patterns that differ from those observed in brain and testis. Our study shows a regulated expression of Fmr1, both at mRNA and protein levels, during rat follicular development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

et al. 2013

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“…These comparisons imply that the mammalian gene family probably arose by duplication from a common ancestor similar to the dFMR1 gene. Consistently, dFMRP displays conserved RNA-binding domains; tissue and subcellular expression patterns; and functional roles in mRNA trafficking and negative translational regulation (Banerjee et al, 2007;Epstein et al, 2009;Estes et al, 2008;Reeve et al, 2005;Zhang et al, 2001;. Moreover, Drosophila that lack the dFMR1 gene (dfmr1 knockouts) closely recapitulate FXS symptoms in a wide range of molecular, cellular and behavioral phenotypes (Bolduc et al, 2008;Dockendorff et al, 2002;Gatto and Broadie, 2009a;McBride et al, 2005;Pan et al, 2004).…”

Section: Introductionmentioning

confidence: 92%

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Coffee

Tessier

Woodruff

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYFragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

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“…The members of the FMRP family act in the control of RNA translation in the nervous system (Epstein et al, 2009;Jin et al, 2004a;Jin et al, 2004b) and in the ovaries (Epstein et al, 2009). More interestingly, these proteins have been reported to associate and interact with components of the RNA-induced silencing complex (RISC) including AGO1 and AGO2, two members of the Argonaute protein family, which mediate post-transcriptional control through small RNAs.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, AGO1 and AGO2 can compete for binding with miRNAs and ectopic expression of Aub in the soma competes for the siRNA pathway mediated by AGO2 (Specchia et al, 2008). Such promiscuity, the known role of the FMRP protein family in small RNA metabolism (Ascano et al, 2012a;Ascano et al, 2012b;Epstein et al, 2009;Ishizu et al, 2012) and the presence of transposons in the nervous system, a key target tissue of the FMRP protein family (Lee et al, 2011;Perrat et al, 2013), prompted us to hypothesize the involvement of the Drosophila ortholog dFmr1 protein in the piRNA pathway.…”

Section: Introductionmentioning

confidence: 99%

The Drosophila fragile X mental retardation protein participates in the piRNA pathway

Bozzetti

Specchia

Cattenoz

et al. 2015

Journal of Cell Science

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RNA metabolism controls multiple biological processes, and a specific class of small RNAs, called piRNAs, act as genome guardians by silencing the expression of transposons and repetitive sequences in the gonads. Defects in the piRNA pathway affect genome integrity and fertility. The possible implications in physiopathological mechanisms of human diseases have made the piRNA pathway the object of intense investigation, and recent work suggests that there is a role for this pathway in somatic processes including synaptic plasticity. The RNAbinding fragile X mental retardation protein (FMRP, also known as FMR1) controls translation and its loss triggers the most frequent syndromic form of mental retardation as well as gonadal defects in humans. Here, we demonstrate for the first time that germline, as well as somatic expression, of Drosophila Fmr1 (denoted dFmr1), the Drosophila ortholog of FMRP, are necessary in a pathway mediated by piRNAs. Moreover, dFmr1 interacts genetically and biochemically with Aubergine, an Argonaute protein and a key player in this pathway. Our data provide novel perspectives for understanding the phenotypes observed in Fragile X patients and support the view that piRNAs might be at work in the nervous system.

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Drosophila Fragile X Protein controls cellular proliferation by regulating cbl levels in the ovary

Cited by 37 publications

References 36 publications

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

The Drosophila fragile X mental retardation protein participates in the piRNA pathway

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