Soxd genes control developmental and adult neurogenesis in the hippocampal neurogenic niche

Abstract

During the development of the dentate gyrus (DG), both at embryonic and postnatal stages, radial glial cells (RGCs) and neural progenitors proliferate and generate mature granule neurons, the principal neuron of the DG. In an unique way, in the adult DG, a subpopulation of progenitors with a radial morphology are retained in a quiescent state as adult radial glial-like cells (RGLs) in the subgranular zone (SGZ) of the DG and continue to produce new granule neurons throughout adult life. This raises questions about when and how adult RGLs are generated in the DG, which are essential questions to understand how neurogenic niches are generated and maintained in the adult brain. HMG-box transcription factors of Sox family genes could be at the core of those processes, as many of them have essential regulatory functions in both developmental and adult neurogenesis. In this study, we have focused on SoxD transcription factors (Sox5 and Sox6) in DG neurogenesis, as our laboratory has previously shown that they play a critical role in regulating cell cycle progression in progenitor cells and that they are expressed in the SGZ, both during DG development and in adulthood. We describe now that during DG development both Sox5 and Sox6 are persistently expressed in RGCs/RGLs and that their expression gradually turns off along the progression of those cells towards the neuronal lineage. By conditional deletion of Sox5 and Sox6 from early central nervous system development, we have determined that Sox5 is required for RGCs/RGLs to enter the quiescent state during postnatal development. Thus, deleting Sox5 expression during development results first in an increase in hippocampal neurogenesis in young adults and then, in mature adults, leads to an exhaustion of RGLs pool. Furthermore, we have found that BMP signaling target, Id2, could be mediating Sox5-regulated quiescence acquisition during DG development. Furthermore, we have found that Sox6 alone is less required than Sox5 for the development of DG, at least during first three postnatal weeks. Interestingly, selective creERT/tamoxifen-induced deletion of SoxD genes in the adult DG, showed that both Sox5 and Sox6 are required for RGLs to transit from quiescent into active proliferative states, and consequently they are needed for adult neurogenesis. Taken together, our results prove that the transition from developmental RGCs into adult RGLs during DG development is regulated by Sox5. These results set up the basis to further explore Sox5 direct targets to understand the molecular mechanism that involve how adult neurogenesis is specifically generated at certain brain areas and how could we modulate the neurogenic process in pathological and ageing brains.