Date of Award

Summer 8-14-2015

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Iqbal Ahmad

Abstract

Emerging evidence has shown that miRNA-mediated gene regulation plays an important role in the development of the central nervous system (CNS). One of the developmental mechanisms may involve let-7 miRNAs and their up-stream regulator, Lin28a and Lin28b in regulating neural stem cells (NSCs). Recently, let-7 has been observed to influence the differentiation of NSCs along neuronal versus glial lineage. However, there is also a report suggesting that the neurogliogenic decision is independent of let-7. These paradoxical results might represent contextual roles of let-7 and lin28 during the CNS development. We have tested this premise in the mammalian retina, a reliable CNS model, during late histogenesis when neurons and the sole glia of the retina, Müller glia (MG), are generated by retinal progenitors cells (RPCs). Using the perturbation of let-7 and Lin28 function analyses in in vitro and ex vivo models of late retinal histogenesis, we observed that let-7 did not influence the neurogliogenic decision; it facilitated the differentiation of RPCs into both neurons and MG. We demonstrated that one of the mechanisms by which let-7 promoted RPCs differentiation was by targeting transcripts corresponding to Hmga2, a high mobility group AT-hook 2 protein, which is known to regulate RPC self-renewal. A similar role for Lin28b emerged when we perturbed its function; it facilitated RPC maintenance and thus influenced their differentiation regardless of the neuronal or glial lineages. However, perturbation of function of Lin28a, whose expression persisted during late retinal histogenesis, influenced RPC differentiation into neurons and MG. For example, the gain of function of Lin28a promoted neurogenesis at the expense of gliogenesis. Taken together, our observations suggest an important role for the Lin28-let-7-Hmga2 axis in the regulation of RPCs, where the expression of lin28a versus lin28b may determine the outcome of the differentiation, orchestrated by let-7, along the neuronal and/or glial lineage(s).

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