Musashi1 and miR-137 antagonism: impact on neurogenesis and diseases

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Adult neurogenesis is fundamental to brain function with important roles in memory and repair. During neurogenesis, dramatic physiological and morphological alterations take place due to coordinated changes in gene expression driven by specific regulators. Dysregulation can ultimately lead to reduced repair, neurodegenerative diseases and brain tumor development. We identified a molecular switch between self-renewal and differentiation having as central players Musashi1 and miR-137. These regulators have opposite expression patterns and functions. Musashi1 (Msi1) is a stem-cell protein implicated in self-renewal while miR-137 functions as a neurogenic miRNA. Msi1 and miR-137 interact at two different levels. First, miR-137 represses Msi1. Second, genomic analyses revealed that Msi1 and miR-137 regulate in opposite directions a large set of target genes implicated in cell migration, neuronal differentiation and cell morphogenesis. We propose that the balance between Msi1 and miR-137 is a key factor in cell fate decisions. In our antagonistic model, Msi1 promotes self-renewal mainly by increasing the expression of targets shared with miR-137 while miR-137 drives differentiation using a double negative switch, inhibiting Msi1 and also the their shared targets. In Aim 1, we will use genomic analyses to build an extended regulatory network for Msi1 and miR-137. We will establish connections (via regulatory, functional or genetic associations) between Msi1/miR-137 shared and unique targets to other genes displaying changes in expression during neurogenesis and identify other regulators that potentially function as partners of Msi1 and miR-137. In Aim 2, we will investigate two scenarios relevant to Alzheimer’s and glioblastoma development: 1) Msi1 inhibition is critical to miR-137 function in differentiation, 2) if miR-137 high expression is required to maintain the neuronal phenotype and 3) if an increase in Msi1 expression in differentiated cells could trigger cell cycle re-entry and repression of genes that maintain the neuronal phenotype. Next, to further support our model of antagonism, we will check if inhibition of miR-137 increases Msi1 expression in hippocampal neurons and if the alterations triggered by miR-137 inhibition can be “neutralized” by silencing Msi1.