Bone morphogenetic protein signaling regulates Id1 mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module.

In the telencephalon of adult zebrafish, the inhibitor of DNA binding 1 (id1) gene is expressed in radial glial cells (RGCs), behaving as neural stem cells (NSCs), during constitutive and regenerative neurogenesis. Id1 controls the balance between resting and proliferating states of RGCs by promoting quiescence. Here, we identified a phylogenetically conserved cis-regulatory module (CRM) mediating the specific expression of id1 in RGCs. Systematic deletion mapping and mutation of conserved transcription factor binding sites in stable transgenic zebrafish lines reveal that this CRM operates via conserved smad1/5 and 4 binding motifs (SBMs) under both homeostatic and regenerative conditions. Transcriptome analysis of injured and uninjured telencephala as well as pharmacological inhibition experiments identify a crucial role of bone morphogenetic protein (BMP) signaling for the function of the CRM. Our data highlight that BMP signals control id1 expression and thus NSC proliferation during constitutive and induced neurogenesis. (c) AlphaMed Press 2020 SIGNIFICANCE STATEMENT: In the adult brain, to maintain a continuous supply of new neurons and to avoid the exhaustion of neural stem cells pool, a tight control between quiescence and proliferation is crucial. id1 gene controls the balance between dividing and resting neural stem cells by promoting quiescence. We identified a regulatory sequence of id1, which mediates the input from the BMP signaling into the adult neural stem cells. This regulatory sequence has a high potential to serve as an interface, which will permit to alter the balance between proliferation and maintenance of stem cells in experimental as well as medical applications.