The function of the zinc finger transcription factor Insm1 in neuronal progenitors

Abstract

The Insulinoma-associated 1 (Insm1) zinc finger transcription factor is highly expressed in the embryonic nervous system and its expression is maintained in the neurogenic areas of the adult brain. Insm1 is a direct target of Ascl1 and has been shown to be important for neuronal differentiation (Wildner et al., 2008; Farkas et al., 2008; Masserdotti et al., 2015; Monaghan et al., 2017). However, the understanding of Insm1 molecular network has remained limited. Here, I sought to undertake a genomic approach to decipher Insm1-dependent molecular mechanisms controlling the progression of neuronal progenitor cells. To this end, I generated datasets of Insm1-dependent expression profiling and its genomic binding profile. Interestingly, Insm1 occupies genomic regions located nearby genes of the Notch signaling pathway. In vivo and in vitro studies showed that mutation of Insm1 in neuronal progenitor cells results in upregulation of Notch signaling components, such as Notch1, Dll1 and Hes1. In vitro analyses illustrate that Insm1 directly represses the expression of these genes. I propose that Insm1 represses the progenitor program downstream of Ascl1 in neurogenesis. Importantly, I show that Insm1 exerts its functions by directly controlling the expression of neuronal target genes and repressing non-neuronal genes. Altogether, this genomic analysis reveals the complex molecular program regulated by Insm1 for the correct establishment of neuronal differentiation through both genetic and epigenetic mechanisms.