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Title:Neuronal FMRP: facilitating learning in a critical brain network for zebra finch song acquisition and regulating synaptic miRNAs spatio-temporally
Author(s):Winograd, Claudia
Director of Research:Ceman, Stephanie S.
Doctoral Committee Chair(s):Ceman, Stephanie S.
Doctoral Committee Member(s):Clayton, David F.; George, Julia M.; DeThorne, Laura S.
Department / Program:School of Molecular & Cell Bio
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Fragile X Mental Retardation Protein (FMRP)
Fragile X Syndrome
zebra finch
RA nucleus
song learning
microRNA (miRNA)
protein translation regulation
synaptic protein translation
Abstract:Fragile X syndrome (FXS) is a genetic disease caused by absent expression of the normal fragile X protein FMRP, presenting with a constellation of features including intellectual disability, connective tissue abnormalities, and impaired vocalization (speech and language). FMRP is an RNA-binding protein, and animal models of FXS present with abnormalities in protein translation. This work will address the roles of FMRP in the development of a neural circuit for vocalization, and in protein translation regulation via the microRNA (miRNA) pathway. Humans are vocal learners, meaning we must hear normal adult vocalization during a critical period in development in order to learn this vocalization properly. Because FXS has both impaired learning and atypical vocalization, it is conceivable that these two features are linked by impaired vocal learning. Our hypothesis is that FMRP is necessary for normal vocal learning. An established model for vocal learning, and thereby ideal for studying the vocal abnormalities of FXS in order to deduce the molecular role of FMRP in vocal learning, is the songbird zebra finch Taeniopygia guttata. In this dissertation I present work that shows expression of the zebra finch FMRP in brain regions critical for normal song learning. Furthermore, I show that this expression is variable across development, supporting the argument for a role of FMRP in song learning. Moreover, I show that this variable expression is not due to singing activity alone. Finally, I present preliminary work developing a genetic tool with which to generate a zebra finch model of FXS. In order to study more thoroughly the role of FMRP in neural development, I will then shift focus to the role of this protein in protein translation regulation via the miRNA pathway. miRNAs are small, genomically-encoded RNAs that regulate translation of target mRNAs, generally by translation suppression of these target mRNAs. It is unknown how miRNAs are regulated in neurons both spatially and temporally. Studies in our and our colleagues’ labs have shown association of FMRP with protein and RNA members of the miRNA pathway. Furthermore, phosphorylated FMRP (P-FMRP) has a suppressive role in protein translation and is present in neuronal dendritic transport granules. Our lab has observed an increased association of P-Fmrp with precursors to miRNAs (pre-miRs) along with a decreased association with Dicer, the rate-limiting enzyme in miRNA biogenesis from pre-miRs, both in comparison with FMRP. Our hypothesis is that P-FMRP transports pre-miRs to dendritic spines, protecting them from Dicer until a specific neural signal indicates necessity for continuation of the miRNA pathway, thereby assisting in spatio-temporal regulation of the miRNA pathway. In contribution to the development of this FMRP-miRNA regulation hypothesis, this dissertation presents data on association of FMRP with other proteins in the miRNA pathway. Notably, some of these associations are affected by phosphorylation status of FMRP. Furthermore, preliminary work is presented that shows that while P-FMRP associates with pre-miRs in mouse brain, FMRP most likely does not bind to these pre-miRs directly.
Issue Date:2013-05-24
Rights Information:Copyright 2013 Claudia Winograd. Permission to use all figures and text from "Exploring the Zebra Finch Taeniopygia guttata as a Novel Animal Model for the Speech-Language Deficit of Fragile X Syndrome", in a Springer book, license number 2818370032752; Chapter 2 is allowed to be used in this dissertation as a privilege of publishing in Elsevier journals
Date Available in IDEALS:2013-05-24
Date Deposited:2013-05

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