Transcriptional regulation of intermediate neuronal progenitor cell generation during telencephalic development

L Harris1, O Zalucki1 and M Piper1,2

  1. The School of Biomedical Sciences, The University of Queensland
  2. Queensland Brain Institute, The University of Queensland

The principal class of progenitor cells in the developing rodent forebrain are the radial glia. During embryogenesis, these cells predominantly generate neurons through the production of intermediate neuronal progenitors (IPCs). Recent reports have begun to elucidate the factors that drive the progression of radial glia into IPCs, highlighting that proteins such as Inscuteable, a regulator of spindle orientation, are central to this process. However, despite these advances, our understanding of the transcriptional regulation of IPC production remains limited. Here, we examined IPC production using mice lacking the transcription factor nuclear factor one x (Nfix). Previous work has demonstrated that mice lacking Nfix display defects in astrocytogenesis. Here, we demonstrate that, within the dorsal telencephalon of Nfix-/- mice, the radial glial population was expanded, and that there was delayed generation of IPCs. Moreover, the expansion of the radial glial pool and delayed generation of IPCs in Nfix-/- mice prolonged the neurogenic window and led to an increased number of neurons in the CA regions of the postnatal hippocampus as well as within the neocortex. Furthermore, double Nfix-/-Nfib-/- conditional knockout mice demonstrated a more severe phenotype, supporting a cell autonomous role for NFIs in promoting IPC production. Mechanistically, bioinformatic analyses, coupled with the investigation of spindle orientation during radial glial cell division, implicate NFIX-mediated inscuteable expression as a critical factor in the generation of IPCs during cortical development. Our results indicate that the transcriptional regulation of inscuteable by NFIX plays a central role in orchestrating the transition of radial glia into IPCs during the development of the mammalian brain.