NFIA controls progenitor cell differentiation through repression of the Notch effector Hes1

Abstract

Notch signaling plays a central role in regulating the self‐renewal of progenitors. The transcription factor Nuclear Factor I A (Nfia) has been implicated downstream of Notch in mid‐gestation telencephalic development, regulating the switch towards astrocytic differentiation from radial progenitors. However, a crucial step in this process is the simultaneous repression of Notch signaling which enables subsequent differentiation to occur. How this is regulated is unknown. Here we demonstrate that, in addition to regulating astrocyte‐specific genes, Nfia represses expression of the Notch effector Hes1. During hippocampal development, we find that Nfia‐deficient mice exhibit delays in both neuronal and glial development. Hes1 is significantly up‐regulated in Nfia mutant hippocampi, and is a direct transcriptional target of Nfia as shown by bioinformatic approaches, chromatin immunoprecipitation analyses and in vitro transcriptional assays. Thus, Nfia promotes differentiation of progenitors via complementary mechanisms, through activation of neuronal‐ and glial‐specific genes and via repression of Notch signaling.