Cerebellar granular neuron progenitors exit their germinative niche via Barhl1 mediated silencing of T-Cell Factor transcriptional activity

Abstract

T-Cell Factors (TCFs) are the main transcriptional effectors of Wnt/beta-catenin signaling. TCF responsiveness is a hallmark of self-renewal in mouse embryonic, and adult, neural stem cells (NSC). However, in vivo contribution(s) of TCF activities in long-lived NSCs are poorly understood. Granule neuron progenitors (GNP) in the upper rhombic lip (URL) are long-lived NSCs which express Atoh1 and generate cerebellar granule neurons. Using functional and transcriptomic approaches in amphibian, we demonstrate that TCFs are active in the URL, and are strictly necessary for the emergence and maintenance of the GNP germinative zone. We identify BarH-like 1 (Barhl1), a direct target of Atoh1, as a gate keeper for GNP exit from the URL, through silencing of TCF transcriptional activity. Our transcriptomic and in silico analysis identifies Barhl1/TCF URL target genes, and confirms our functional data. Our study provides in vivo evidence that inhibition of TCF repressive activity is necessary for maintenance of the URL, a long-lived neural germinative niche.