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.

Public Health Relevance

Abnormal structure of brain synapses has been linked to intellectual disabilities and autism spectrum disorders. The results of this study are anticipated to reveal a new mechanism for how synapse growth and structural plasticity is regulated and may be altered in neuropsychiatric disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH095266-02
Application #
8458758
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Rosemond, Erica K
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$30,912
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wigington, Callie P; Williams, Kathryn R; Meers, Michael P et al. (2014) Poly(A) RNA-binding proteins and polyadenosine RNA: new members and novel functions. Wiley Interdiscip Rev RNA 5:601-22