The transcription factor COUP-TFI is required for hippocampal development and dentate granules neurogenesis

The archicortex, and in particular the hippocampus, integrates a wide range of signals through a particular laminar organization in which controlled expression of different transcription factors plays a major role during development. The nuclear receptor COUP-TFI is involved in many aspects of cortical neurogenesis, from arealization to cell-type specification and axon formation. Interestingly, COUP-TFI is expressed in a graded rostro-caudal manner in the hippocampus, with high levels in the neuroepithelium of the dentate gyrus (DG) and in the mature granule cell layer. To assess its role in hippocampal development, two independent conditional lines, in which COUP-TFI is either inactivated in all cortical progenitors or exclusively in post-mitotic neurons, were used. While absence of COUP-TFI function in post-mitotic neurons has a minor effect on the overall hippocampal development, loss-of-function of COUP-TFI in cortical progenitors leads to dramatic malformations in the growth and maturation of the hippocampus and dentate gyrus. In particular, the temporal progression of granule cell differentiation is affected resulting ultimately in decreased adult neurogenesis in adult COUP-TFI mutant mice. Furthermore, various components of the Notch-Delta signaling pathway required for the different steps of granule differentiation are altered, leading to an abnormal distribution of progenitors and immature granule cells during development of the dentate gyrus. Altogether, these results indicate that COUP-TFI plays an essential role in regulating particular aspects of dentate granule cell neurogenesis, and, importantly, propose COUP-TFI as a novel factor required in maintaining the adult neuronal stem cell niche.