Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

Abstract

During forebrain development, radial glia generate neurons through the production of intermediate progenitor cells (IPCs). The production of IPCs is a central tenet underlying the generation of the appropriate number of cortical neurons, but the transcriptional logic underpinning this process remains poorly defined. Here, we examined IPC production using mice lacking the transcription factor nuclear factor I/X (Nfix). We show that Nfix deficiency delays IPC production and prolongs the neurogenic window, resulting in an increased number of neurons in the postnatal forebrain. Loss of additional Nfi alleles (Nfib) resulted in a severe delay in IPC generation while, conversely, overexpression of NFIX led to precocious IPC generation. Mechanistically, analyses of microarray and ChIP-seq datasets, coupled with the investigation of spindle orientation during radial glial cell division, revealed that NFIX promotes the generation of IPCs via the transcriptional upregulation of inscuteable (Insc). These data thereby provide novel insights into the mechanisms controlling the timely transition of radial glia into IPCs during forebrain development.

Combined allelic dosage of Nfia and Nfib regulates cortical development

“…Although mRNA expression analyses of Nfia and Nfib knockout embryos have revealed several common downstream targets (Barry et al, 2008;Betancourt et al, 2014;Harris et al, 2016;Piper et al, 2009Piper et al, , 2010Piper et al, , 2014, the overlap of these factors in regulating downstream targets and pathways remained unclear. We therefore analysed mRNA-sequencing data from the cerebral cortex of E16 Nfia and Nfib knockout mice and their corresponding wildtype littermates.…”

The function of NFIX during developmental and adult neurogenesis

“…As a result, in Nfix -/-mice, radial glial stem cells undergo more self-expanding divisions, thereby extending the neurogenic period. This results in the production of more neurons and postnatal macrocephaly in this line without any observed negative affects on neuronal survival (Chapter 3) Heng et al, 2014;Harris et al, 2016a). In contrast, in AH-NSCs we found that the deletion of Nfix does not affect the production of IPs ( NFIX has been hypothesised to be a central factor in maintaining AH-NSC quiescence.…”

“…Two pivotal differences are the relative stages of neuronal lineage progression controlled by NFIX and the effect that Nfix deletion has on neuronal survival. In the developing dorsal forebrain, NFIX promotes the asymmetric division of radial glial stem cells and the subsequent production of IPs (Harris et al, 2016a), which is the earliest fate choice that occurs during neuronal differentiation. As a result, in Nfix -/-mice, radial glial stem cells undergo more self-expanding divisions, thereby extending the neurogenic period.…”

“…During brain development NFIX promotes neuronal differentiation, with abnormal expression associated with multiple neurodevelopmental disorders (Malan et al, 2010;Yoneda et al, 2012;Heng et al, 2014;Harris et al, 2016a;Deciphering Developmental Disorders, 2017). The increased expression of NFIX in IPs and neuroblasts ( Figure 5.1I) suggests that NFIX may play a central role in regulating neuronal differentiation in the adult hippocampus.…”

“…In the developing dorsal telencephalon (Chapter 3) Heng et al, 2014;Harris et al, 2016a) and cerebellum of mice (Piper et al, 2011;Fraser et al, 2016), NFIX is essential for the timely differentiation of both neurons and astrocytes. The importance of NFIX for mouse brain development appears conserved during human brain development, as patients with NFIX mutations present with one of two developmental disorders characterised by a substantial brain phenotype.…”