let-7 microRNA regulates neurogliogenesis in the mammalian retina through Hmga2

Abstract

One of the well established aspects of the development of the central nervous system (CNS) is that neurogenesis precedes gliogenesis. However, the mechanism underlying this temporal switch between the two distinct lineages is poorly understood. It is thought that let-7, a heterochronic miRNA, may help neural stem cells (NSCs) choose between the neuronal and glial lineages. Here, we have tested the premise in the retina, a simple and accessible CNS model, where neurogliogenic decision takes place postnatally during late histogenesis. A positive correlation was observed between the temporal induction of let-7 expression and differentiation of late born neurons and Müller glia (MG), the sole glia generated by retinal progenitor cells (RPCs). Examination of let-7's involvement in late histogenesis by the perturbation of function approaches revealed that let-7 facilitated differentiation of both neurons and MG, without preference to a particular lineage. We demonstrate that let-7's positive influence on neuronal and MG differentiation is likely achieved by inhibiting the expression of Hmga2, the DNA architecture protein involved in the self-renewal of neural progenitors. Thus, our observations suggest that let-7 promotes differentiation, regardless of the neuronal or glial lineage, shifting the balance from RPCs' maintenance to their differentiation in the developing retina.