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B.S., Rutgers University
School of Engineering - 2008
Thesis Advisor: Mladen-Roko Rasin, M.D., Ph.D.
Graduate Program in Neuroscience
CABM, Room 010
Wednesday, December 11, 2013
Prior to neurogenesis the neuroepithelial neural stem cell (NSC) lineage divides symmetrically during the expansion phase to generate the proper number of neurogenic stem cells. Next, neuroepithelial cells (NECs) differentiate to the radial glia (RG) NSC lineage, which asymmetrically divide to generate subpopulations of cortical projection neurons, defining the onset of neurogenesis. The NEC to RG transition signals the beginning of neurogenesis and, ultimately, the number of cortical projection neuron progeny that differentiate through initiation of specific gene expression programs. However, the posttranscriptional mechanisms underlying the NEC to RG transition and postmitotic differentiation are not fully understood. Interestingly, RNA binding proteins (RBPs) occupy a unique position to dynamically regulate the transcriptome-to-proteome transition via control of mRNA splicing, subcellular transport, stability and translation. Therefore, we identified the RBP, Hu antigen R (HuR), as highly expressed in NECs, early RG and postmitotic neurons throughout neocortical development.
We found that genetic deletion of HuR resulted in decreased NSC cell cycle re-entry, agenesis of the corupus callosum (AgCC) and an overall decrease in dendrite length and branching of lower layer neurons. Interestingly, HuR bound layer specific forkhead box transcription factor mRNA dynamically throughout neurogenesis and differentially controlled temporally specific posttranscriptional processing of forkhead box transcription factors Foxp1 and Foxp2. We found that HuR regulated the NSC cell cycle by temporally selective inhibition of Foxp1 mRNA translation. Indeed, when HuR was deleted in developing neocortices premature expression of FOXP1 protein was detected in mitotic NSCs. Furthermore, when FOXP1 protein was artificially over expressed in NSCs by in utero electroporation we observed reduced cell cycle re-entry. Additionally, we also found that HuR deletion led to reduced FOXP2 protein expression. Importantly, ectopic FOXP2 expression in shRNA mediated HuR knockdown in primary neuronal cultures resulted in a phenotypic rescue of reduced dendritogenesis. Finally, we observed that HuR interacted with the eukaryotic initiation factor 2 alpha kinase 4 (eIF2ak4) and dynamically regulated the phosphorylation of translation factors and ribosomal protein assembly. These findings reveal temporally specific regulation of distinct transcriptome elements by HuR in NSCs and postmitotic neurons during the NEC to RG transition and postmitotic neuron specification.