Cerebellar granular neuron progenitors exit their germinative niche via BarH-like1 activity mediated partly by inhibition of T-Cell Factor

Cerebellar granule neuron progenitors (GNP) originate from the upper rhombic lip (URL), a germinative niche whose developmental defects produce human diseases. T-Cell Factors (TCF) responsiveness and Notch dependence are hallmarks of self-renewal in neural stem cells. TCF activity together with transcripts coding for proneural genes repressors hairy and enhancer of split (hes/hey), are detected in the URL. However, their functions and regulatory modes are undeciphered. Here we established amphibian as a pertinent model to study vertebrate URL development. Amphibians long-lived URL is Tcf active, while the External Granular layer (EGL) is non-proliferative and expresses hes4/5 genes. Using functional and transcriptomic approaches, we show that Tcf activity is necessary for URL emergence and maintenance. We establish that the transcription factor Barhl1 controls GNP exit from the URL acting partly through direct Tcf inhibition. Identification of Barhl1 target genes argues that besides Tcf, Barhl1 inhibits transcription of hes5 genes independently of Notch signaling. Observations in amniotes suggest a conserved role of a Barhl in maintenance of the URL/EGL via coregulation of TCF and hes/hey genes.