In utero gene transfer system for embryos before neural tube closure reveals a role for Hmga2 in the onset of neurogenesis

During the early stage of mammalian neural development, neuroepithelial cells (NECs) proliferate and increase their pool size during the expansion phase, and then they switch their fate and become neurogenic radial glial progenitors (RGPs). The timing of this switch is strictly regulated to determine the number of progenitors and differentiated cell types that consist the brain. The molecular mechanisms underlying this switch remained poorly understood, however, in part due to the difficulty to manipulate genes in NECs before their switch into RGPs. In this study, we established a simple and efficient method to manipulate gene expression in mouse neocortical NECs in the expansion phase by in utero injection of viral vectors before neural tube closure at mouse embryonic day (E) 7.0 and 8.0. This method also enables us to manipulate gene expression in other ectodermal and endodermal cells at this stage. By the use of this method, we show that knockdown of Hmga2, a chromatin-associated protein, inhibits the onset of neurogenesis in neocortical neural progenitors. Mechanistically, Hmga2 activates a set of target genes of Polycomb group proteins, which are known to suppress neurogenic genes in cortical progenitors. Taken together, this study provides a novel method for manipulating genes in the early stage of mouse ectodermal and endodermal organogenesis and uncovers a key molecule that gives rise to neurogenic progenitors in the developing mouse neocortex.