Modulation of RhoA Signaling by the mRNA Binding Protein hnRNPQ1

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DESCRIPTION (provided by applicant): Abnormal neuronal morphology is a common theme among intellectual disabilities and autism despite the diverse pathological mechanisms underlying these disorders. Specifically, numerous neuropsychiatric diseases have been demonstrated to present with abnormalities in the morphology of dendritic spines, small actin-rich compartments that protrude from the dendrites. The small GTPase, RhoA, a well-characterized regulator of actin dynamics, has been suggested to play a critical role in regulating the morphology of these actin-rich spines. Our lab has revealed that the mRNA binding protein hnRNPQ1 interacts with RhoA mRNA and downregulation of hnRNPQ1 increases steady state RhoA protein levels without increasing RhoA mRNA levels in cultured cells. Additionally, depletion of hnRNPQ1 causes phenotypes associated with increased RhoA signaling in cultured cell lines and primary neuronal cultures. Furthermore, the reduction in hippocampal neuron dendritic spine density observed upon hnRNPQ1 depletion can be rescued by pharmacological inhibition of the RhoA signaling pathway. These preliminary studies warrant investigation of the possible role of hnRNPQ1 in mediating RhoA protein synthesis and signaling in primary neuronal cultures. The proposed research aims to characterize the interaction between hnRNPQ1 protein and RhoA mRNA (Specific Aim 1) and determine whether hnRNPQ1 regulates RhoA mRNA translation locally in dendrites (Specific Aim 2). Additionally, the role of hnRNPQ1 in regulating dendritic spine morphology and RhoA signaling will be assessed in primary neuronal cultures by depleting hnRNPQ1 and analyzing dendritic spine morphological and molecular phenotypes (Specific Aim 3). We hypothesize that hnRNPQ1 negatively regulates the local translation of RhoA mRNA in dendrites, therefore modulating dendritic spine morphology through altered RhoA signaling. This study attempts to link RhoA expression regulation to RhoA signaling modulation and consequently synaptic development, maintenance and plasticity, which is currently a critical gap in our knowledge. Studying the mechanisms involved in regulating dendritic spine morphogenesis will improve our understanding of intellectual disabilities and autism, which will aid in the development of new treatments for these disorders.