Analysis of downstream targets of PAX6 and LHX2, fundamental regulators of the developing mammalian neocortex.

Abstract

The transcription factors PAX6 and LHX2 play fundamental roles in mammalian cerebral cortical development. Loss of either factor causes depletion of the cortical progenitor pool and reduction of neurogenesis of later-born cortical neurons. We compared the chromatin occupancy of PAX6 and LHX2 and transcriptional dysregulation upon loss of each factor to analyze whether they function via common gene regulatory networks. We identified common direct and indirect targets that were dysregulated either concordantly or discordantly, based on whether their expression showed similar up- or downregulation upon loss of either factor. Finally, we examined single-cell RNA-seq datasets from neocortical progenitors to identify the cell types within which each common direct/indirect and concordantly/discordantly regulated target gene is expressed as cortical progenitors undergo neurogenesis. Our analysis shows that PAX6 and LHX2 have several common targets that suggest similar pathways for progenitor maintenance, but the regulation of neurogenesis may occur via at least partially non-overlapping pathways. Furthermore, each factor functions to suppress the expression of a set of common Cajal-Retzius cell-specific and interneuron-specific genes which are not normally expressed by cortical progenitors. Together, our analysis offers experimentally testable hypotheses for how PAX6 and LHX2 may execute their critical roles.