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Timed specificity of the neocortical translation machinery is regulated by an ELAV RNA-binding protein and WNT3 secreted from thalamic axons

by
Matthew L. Kraushar
B.A., Columbia University - May 2008

Thesis Advisor: Mladen-Roko Rasin, M.D., Ph.D.
Graduate Program in Neuroscience

Center for Advanced Biotechnology & Medicine (CABM)
Room 010
Piscataway

Friday, April 17, 2015
3:00 p.m.


Abstract

Within the brainís neocortex originates our most evolutionarily advanced complex cognitive functions. The diverse subpopulations of neural stem cells and post-mitotic neurons underlying these intricate circuits are molecularly defined in space and time by their patterns of gene expression. Gene expression culminates in protein synthesis via mRNA translation at the level of the ribosome. Therefore, mRNA translation must be tightly spatiotemporally regulated in development for specific mRNAs to generate molecularly defined subpopulations of neocortical neurons. We show that active mRNA translation sites (polysomes) contain ribosomal protein subsets and functionally related mRNAs that undergo dynamic spatiotemporal rearrangements during mouse neocortical development. Ribosomal protein specificity and mRNA translation in the neocortex are regulated intrinsically by an RNA-binding protein, HuR, and extrinsically by the timed arrival of in-growing thalamic axons secreting the morphogen Wingless-related MMTV integration site 3 (Wnt3). HuR and thalamic Wnt3 coordinately regulate translation of essential neocortical mRNAs, such as Foxp2, thereby dictating neocortical neuronal differentiation. This mechanism may enable targeted and rapid spatiotemporal control of mRNA translation in complex developing systems like the neocortex.


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