Subcellular mRNA localization and local translation of Arhgap11a in radial glial progenitors regulates cortical development.

mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in polarized, elongated cells. These features are especially prominent in radial glial cells (RGCs), which are neural and glial precursors of the developing cerebral cortex and scaffolds for migrating neurons. Yet the mechanisms by which subcellular RGC compartments accomplish their diverse functions are poorly understood. Here, we demonstrate that mRNA localization and local translation of the RhoGAP ARHGAP11A in the basal endfeet of RGCs control their morphology and mediate neuronal positioning. Arhgap11a transcript and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by the 5' UTR. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to the basal endfeet, where ARHGAP11A is locally synthesized. This translation is essential for positioning interneurons at the basement membrane. Thus, local translation spatially and acutely activates Rho signaling in RGCs to compartmentalize neural progenitor functions.

Non-muscle myosins control radial glial basal endfeet to mediate interneuron organization.

Radial glial cells (RGCs) are essential for the generation and organization of neurons in the cerebral cortex. RGCs have an elongated bipolar morphology with basal and apical endfeet that reside in distinct niches. Yet, how this subcellular compartmentalization of RGCs controls cortical development is largely unknown. Here, we employ in vivo proximity labeling, in the mouse, using unfused BirA to generate the first subcellular proteome of RGCs and uncover new principles governing local control of cortical development. We discover a cohort of proteins that are significantly enriched in RGC basal endfeet, with MYH9 and MYH10 among the most abundant. Myh9 and Myh10 transcripts also localize to endfeet with distinct temporal dynamics. Although they each encode isoforms of non-muscle myosin II heavy chain, Myh9 and Myh10 have drastically different requirements for RGC integrity. Myh9 loss from RGCs decreases branching complexity and causes endfoot protrusion through the basement membrane. In contrast, Myh10 controls endfoot adhesion, as mutants have unattached apical and basal endfeet. Finally, we show that Myh9- and Myh10-mediated regulation of RGC complexity and endfoot position non-cell autonomously controls interneuron number and organization in the marginal zone. Our study demonstrates the utility of in vivo proximity labeling for dissecting local control of complex systems and reveals new mechanisms for dictating RGC integrity and cortical architecture.

Local gene regulation in radial glia: Lessons from across the nervous system.

Radial glial cells (RGCs) are progenitors of the cerebral cortex which produce both neurons and glia during development. Given their central role in development, RGC dysfunction can result in diverse neurodevelopmental disorders. RGCs have an elongated bipolar morphology that spans the entire radial width of the cortex and ends in basal endfeet connected to the pia. The basal process and endfeet are important for proper guidance of migrating neurons and are implicated in signaling. However, endfeet must function at a great distance from the cell body. This spatial separation suggests a role for local gene regulation in endfeet. Endfeet contain a local transcriptome enriched for cytoskeletal and signaling factors. These localized mRNAs are actively transported from the cell body and can be locally translated in endfeet. Yet, studies of local gene regulation in RGC endfeet are still in their infancy. Here, we draw comparisons of RGCs with foundational work in anatomically and phylogenetically related cell types, neurons and astrocytes. Our review highlights a striking overlap in the types of RNAs localized, as well as principles of local translation between these three cell types. Thus, studies in neurons, astrocytes and RGCs can mutually inform an understanding of RNA localization across the nervous system.