The cellular mechanisms that regulate self-renewal versus differentiation of mammalian neural stem cells are still largely unknown. Clues come from model organisms such as Drosophila, were macromolecular RNA granules are asymmetrically localized to facilitate asymmetric cell divisions. As an example, in the neuroblast, the fly neural stem cell, mRNA for prospero, a proneurogenic transcription factor, is asymmetrically distributed during mitosis so that only one of the daughter cells inherits it. This daughter cell is subsequently conferred a neural fate. Here, we asked whether an RNA complex regulates this process in mammalian neural stem cells. We show that the RNA-binding protein Staufen2 (Stau2) is apically localized in radial glial precursors of the embryonic cortex, where it forms a complex with other RNA-binding proteins including Pumilio2 (Pum2) and DDX1, and the mRNAs for β-actin and the mammalian homologue of prospero, prox1. Perturbation of this complex by functional knockdown of Stau2, Pum2, or DDX1 causes premature differentiation of radial glial precursors into neurons and mislocalization and misexpression of prox1 mRNA. Thus, a Stau2- and Pum2-dependent RNA complex directly regulates localization and, potentially, expression of target mRNAs like prox1 in mammalian neural stem cells, and in so doing regulates the balance of stem cell maintenance versus differentiation.
Asymmetric RNA-Localization in Cortical Precursor Cells: Facilitating Brain Development