Fragile-X Syndrome represents the most common form of hereditary mental retardation. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family of RNA-binding proteins. The dFmr1 gene is the Drosophila ortholog of the human gene (Fmr1) involved in the syndrome (1). Drosophila melanogaster is considered a good model for the study of the molecular mechanism at the bases of the different phenotypes exhibited by patients. Drosophila has a unique fragile X-related gene, the dFmr1 gene, whose mutants exhibit defects in neuronal structure and function, behavior, and germline development, resembling those observed in patients (2,3). During the first part of the project, we identified and validated a new role for the dFmr1 gene in the silencing of transposable elements and repetitive sequences mediated by the piRNA pathway in the gonads (2,4-6). The starting point was the observation that the crystal-Stellate interaction (2), depending on a correct function of the piRNA pathway, was deregulated in dFmr1 mutants. We also demonstrated that dFmr1 interacts genetically and co-localizes with Aubergine and Vasa, two key components of the pathway. We also investigated in detail the genetic and physical interaction of dFmr1 in gonads, looking at the rescue of the “crystal phenotype” in testes and at the fertility of dFmr1 mutants in a genetic background overexpressing genes with a role in the piRNA pathway. These results will be useful for clarifying the role of dFmr1 in gonads and even in the nervous system (6-8). During the last part of the project we analyzed the possible role of the piRNA pathway in the nervous system, gaining information on its presence in this tissue and on the function of dFmr1 in the pathway. In addition, we started studying a possible physiological role of transposable elements during the brain development. Our research intends to clarify if a common molecular base is involved in the majority of the phenotypes exhibited by dFmr1 mutants due to genome instability.
Drosophila melanogaster as a model to study the role of FMRP protein, involved in the Fragile-X syndrome, in the piRNA-mediated genome stability
Valeria Specchia;Simona D’Attis;Antonietta Puricella;Maria Pia Bozzetti
2019-01-01
Abstract
Fragile-X Syndrome represents the most common form of hereditary mental retardation. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family of RNA-binding proteins. The dFmr1 gene is the Drosophila ortholog of the human gene (Fmr1) involved in the syndrome (1). Drosophila melanogaster is considered a good model for the study of the molecular mechanism at the bases of the different phenotypes exhibited by patients. Drosophila has a unique fragile X-related gene, the dFmr1 gene, whose mutants exhibit defects in neuronal structure and function, behavior, and germline development, resembling those observed in patients (2,3). During the first part of the project, we identified and validated a new role for the dFmr1 gene in the silencing of transposable elements and repetitive sequences mediated by the piRNA pathway in the gonads (2,4-6). The starting point was the observation that the crystal-Stellate interaction (2), depending on a correct function of the piRNA pathway, was deregulated in dFmr1 mutants. We also demonstrated that dFmr1 interacts genetically and co-localizes with Aubergine and Vasa, two key components of the pathway. We also investigated in detail the genetic and physical interaction of dFmr1 in gonads, looking at the rescue of the “crystal phenotype” in testes and at the fertility of dFmr1 mutants in a genetic background overexpressing genes with a role in the piRNA pathway. These results will be useful for clarifying the role of dFmr1 in gonads and even in the nervous system (6-8). During the last part of the project we analyzed the possible role of the piRNA pathway in the nervous system, gaining information on its presence in this tissue and on the function of dFmr1 in the pathway. In addition, we started studying a possible physiological role of transposable elements during the brain development. Our research intends to clarify if a common molecular base is involved in the majority of the phenotypes exhibited by dFmr1 mutants due to genome instability.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
