Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development

Abstract

mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in highly polarized and elongated cells. These features are especially prominent in radial glial cells (RGCs), which serve as neural and glial precursors of the developing cerebral cortex, and scaffolds for migrating neurons. Yet the mechanisms by which distinct sub-cellular compartments of RGCs accomplish their diverse functions are poorly understood. Here, we demonstrate that subcellular RNA localization and translation of the RhoGAP Arhgap11a controls RGC morphology and mediates cortical cytoarchitecture. Arhgap11a mRNA and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by a 5′UTR cis-element. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to basal structures, where ARHGAP11A is locally synthesized. Thus, RhoA activity is spatially and acutely activated via local translation in RGCs to promote neuron positioning and cortical cytoarchitecture. Altogether, our study demonstrates that mRNA localization and local translation mediate compartmentalization of neural progenitor functions to control brain development.

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

“…Supporting this notion, we recently discovered a Rho GTPase regulator whose local translation in endfeet is critical for their morphology and further for cortical organization. 32 been studied for decades. 36,37 Cumulative studies have produced a wealth of knowledge regarding which transcripts are localized and locally translated, cis-and trans-factors involved in mRNA transport and signals which regulate local gene regulation.…”

A Picture Worth a Thousand Molecules—Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits

“…Similar to the regulatory structure of the 3 -UTR, 5 -UTR cis-elements also have important roles in regulating local protein translation essential for brain development. During laminar development of the neonatal cortex, 5 -UTR-dependent mRNA trafficking and local translation regulate radial glial cell branching and neuronal migration patterns to establish proper cortical lamination (Pilaz et al, 2020). At later developmental stages, 5 -UTR cis-sequences have been implicated in local translation underlying axon growth/pathfinding.…”

Ariadne’s Thread in the Developing Cerebral Cortex: Mechanisms Enabling the Guiding Role of the Radial Glia Basal Process during Neuron Migration

“…Its composition includes collagens, nidogen, perlecan, and laminins [ 36 , 37 ] ( Figure 3 a). Radial glia attachment to the basal lamina occurs at the level of basal endfeet, which altogether tile the basal lamina in the manner of a jigsaw puzzle [ 38 ]. The connection between radial glia basal endfeet and the basal lamina relies on various transmembrane receptors, such as integrins and the Dystrophin-Glycoprotein Complex [ 37 , 39 , 40 ] ( Figure 3 a).…”

“…In addition to these questions, it will be interesting to consider how key molecules mediating the attachment of radial glia to the basal lamina are delivered to basal endfeet. Related to this question, one line of research could focus on the potential importance of mRNA transport and local protein synthesis in that process, two processes known to co-exist in radial glia as described below [ 38 , 43 , 44 , 45 , 46 ].…”

“…This appears to be the case in radial glia as well. Indeed, mRNAs are actively transported to the radial glia basal endfeet via the basal process [ 38 , 43 , 44 , 46 ] ( Figure 4 ). In basal endfeet, these mRNAs can be utilized for local protein synthesis.…”