COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal CXCR4 expression

Abstract

Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it either in granule cell progenitors or in granule neurons. Loss of COUP-TFI function in progenitors leads to decreased granule cell proliferative activity, precocious differentiation and increased apoptosis, resulting in a severe DG growth defect in adult mice. COUP-TFI-deficient cells express high levels of the chemokine receptor CXCR4 and migrate abnormally, forming heterotopic clusters of differentiated granule cells along their paths. Conversely, high COUP-TFI expression levels downregulate CXCR4 expression, whereas increased CXCR4 expression in wild-type hippocampal cells affect cell migration. Finally, loss of COUP-TFI in postmitotic cells leads only to minor and transient abnormalities, and normal CXCR4 expression. Together, our results indicate that COUP-TFI is required predominantly in DG progenitors by modulating expression of the CXCR4 receptor during granule cell neurogenesis and migration.