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dc.contributor.advisorZarnescu, Daniela Cen_US
dc.contributor.authorCallan, Matthew Aron*
dc.creatorCallan, Matthew Aronen_US
dc.date.accessioned2011-10-14T22:37:30Z
dc.date.available2011-10-14T22:37:30Z
dc.date.issued2011
dc.identifier.urihttp://hdl.handle.net/10150/145454
dc.description.abstractFragile X Syndrome (FXS) is the most common form of inherited mental retardation, affecting approximately 1/4000 males and 1/6000 females worldwide. FXS is caused by loss of FMR1 gene expression, resulting in the lack of the protein product, Fragile X protein (FMRP). FMRP is an RNA-binding protein thought to regulate synaptic plasticity by controlling the localization and translation of specific mRNAs in neurons. To determine whether FMRP is also required in early brain development we examined the distribution of cell cycle markers in Drosophila FMR1 (dFmr1) mutant brains compared to wild-type brains. Our results indicate that the loss of dFmr1 leads to a significant increase in the number of mitotic neuroblasts and BrdU incorporation in the brain, consistent with the notion that FMRP controls proliferation in neural stem cells. To determine the role of FMRP in neuroblast division and differentiation, we used Mosaic Analysis with a Repressible Marker (MARCM) approaches in the developing larval brain and found that single dFmr1 neuroblasts generate significantly more neurons than controls. Developmental studies suggest that FMRP also inhibits neuroblast exit from quiescence, or reactivation, in early larval brains, as indicated by misexpression of the G1 to S phase transition marker Cyclin E. We have also identified a novel role for FMRP in the glia surrounding the neuroblasts, indicating that FMRP in these cells contributes to the regulation of neuroblast reactivation via signaling from the supporting glial cells. Our results demonstrate that FMRP is required during brain development to control the exit from quiescence and proliferative capacity of neuroblasts as well as neuron production, which may provide insights into Fragile X Syndrome and other Autism-Spectrum disorders.
dc.language.isoenen_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.subjectAutism Spectrumen_US
dc.subjectFragile Xen_US
dc.subjectGliaen_US
dc.subjectNeural Stem Cellen_US
dc.subjectNeurogenesisen_US
dc.titleNovel Roles for Fragile X Protein in Neurogenesisen_US
dc.typeElectronic Dissertationen_US
dc.typetexten_US
dc.identifier.oclc752261418
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberDavidson, Braden_US
dc.contributor.committeememberBosco, Giovannien_US
dc.contributor.committeememberDixon, Kathleenen_US
dc.identifier.proquest11555
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.namePh.D.en_US
refterms.dateFOA2018-06-17T05:03:22Z
html.description.abstractFragile X Syndrome (FXS) is the most common form of inherited mental retardation, affecting approximately 1/4000 males and 1/6000 females worldwide. FXS is caused by loss of FMR1 gene expression, resulting in the lack of the protein product, Fragile X protein (FMRP). FMRP is an RNA-binding protein thought to regulate synaptic plasticity by controlling the localization and translation of specific mRNAs in neurons. To determine whether FMRP is also required in early brain development we examined the distribution of cell cycle markers in Drosophila FMR1 (dFmr1) mutant brains compared to wild-type brains. Our results indicate that the loss of dFmr1 leads to a significant increase in the number of mitotic neuroblasts and BrdU incorporation in the brain, consistent with the notion that FMRP controls proliferation in neural stem cells. To determine the role of FMRP in neuroblast division and differentiation, we used Mosaic Analysis with a Repressible Marker (MARCM) approaches in the developing larval brain and found that single dFmr1 neuroblasts generate significantly more neurons than controls. Developmental studies suggest that FMRP also inhibits neuroblast exit from quiescence, or reactivation, in early larval brains, as indicated by misexpression of the G1 to S phase transition marker Cyclin E. We have also identified a novel role for FMRP in the glia surrounding the neuroblasts, indicating that FMRP in these cells contributes to the regulation of neuroblast reactivation via signaling from the supporting glial cells. Our results demonstrate that FMRP is required during brain development to control the exit from quiescence and proliferative capacity of neuroblasts as well as neuron production, which may provide insights into Fragile X Syndrome and other Autism-Spectrum disorders.


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