Lysosomal dynamics regulate mammalian cortical neurogenesis

Abstract

Mammalian neocortex formation follows a stereotypical pattern wherein the self-renew and differentiation of neural stem cells are coordinated with diverse organelle dynamics. However, the role of lysosomes in brain development has long been overlooked. Here, we demonstrate the highly dynamic lysosomal quantities, types, and localizations in developing brain. We observed asymmetric endolysosome inheritance during radial glial cell (RGC) division and the increased autolysosomes within intermediate progenitor cells (IPs) and newborn neurons. Disruption of lysosomal function shortens the S phase of the cell cycle and promotes RGC differentiation. Mechanistically, we revealed a post-transcriptional regulation governing ribosome homeostasis and cell-cycle progression through differential lysosomal activity modulation. In the human forebrain organoid, lysosomal dynamics are conserved; specifically, during the mitosis of outer subventricular zone RGCs (oRGs), lysosomes are inherited by the progeny without basal process. Together, our results identify the critical role of lysosomal dynamics in regulating mouse and human brain development.

Keywords: asymmetric cell division; cell-cycle progression; human brain organoid; lysosomal dynamics; neural stem cell; neurogenesis; outer subventricular zone radial glial cell; post-transcriptional regulation.