Decoding mixed messages in the developing cortex: translational regulation of neural progenitor fate

Abstract

Regulation of stem cell fate decisions is elemental to faithful development, homeostasis, and organismal fitness. Emerging data demonstrate pluripotent stem cells exhibit a vast transcriptional landscape, which is refined as cells differentiate. In the developing neocortex, transcriptional priming of neural progenitors, coupled with post-transcriptional control, is critical for defining cell fates of projection neurons. In particular, radial glial progenitors exhibit dynamic post-transcriptional regulation, including subcellular mRNA localization, RNA decay, and translation. These processes involve both cis-regulatory and trans-regulatory factors, many of which are implicated in neurodevelopmental disease. This review highlights emerging post-transcriptional mechanisms which govern cortical development, with a particular focus on translational control of neuronal fates, including those relevant for disease.

Figure 1.. Corticogenesis in mice.

A) Schematic of an E14.5 embryonic mouse where the brain and a cross-section of the cortex is visible. B) During early stages of corticogenesis in mice, neuroepithelial cells (yellow) undergo self-renewing divisions before transitioning to radial glial cells (RGCs, orange). RGCs make contact with the apical membrane and cerebrospinal fluid, as well as the basal basement membrane with overlying vasculature (red). RGCs divide symmetrically to self-renew and expand the neural progenitor pool in the ventricular zone (VZ). RGCs divide asymmetrically to produce neurons (green) directly or indirectly through production of an intermediate progenitor (IP, light blue). In mice, IPs primarily undergo terminal neurogenic divisions in the sub-ventricular zone (SVZ). These divisions continue over the course of neurogenesis, but for simplicity, arrows depicting divisions are only shown for early stages. Newborn neurons then use the RGC basal process as a scaffold to migrate and form the various layers of the cortical plate (CP; multi-colored neurons), where they have unique axonal targets.

Figure 2.. Transcriptional priming and post-transcriptional mechanisms to poise progenitors for different cell fates.

A) A radial glial cell (RGC) responds to external cues from 1) cell-matrix adhesions, 2) a migrating neuron, and 3) the ventricle and cerebrospinal fluid (CSF), which induce transcription of mRNAs required for different cell fates. B) A mitotic RGC uses various post-transcriptional regulatory mechanisms to repress mRNAs required for neuronal (green) and intermediate progenitor (IP, blue) fates. C) In a newborn neuron, an RBP-mediated translational repression is relieved by a specialized ribosome required for translation of this pro-neurogenic mRNA (bottom). An RNP granule may eventually be trafficked for local translation (top). D) In a newborn IP, an IP-enriched RBP prevents translational repression of an mRNA transcript required for fate specification (top). The newborn IP also inherited a pro-neurogenic transcript, which is still under repressive control of the bound RBP. These highlight some examples of post-transcriptional regulation of cell fates.

Figure 3.. Specific mechanisms of cis- and trans-encoded translation regulation that influence cell fate.

1) Ribosomes are positioned locally in radial glial endfeet to translate mRNAs in response to environmental cues. 2) Upstream open reading frames (uORFs) can repress canonical ORF translation by inducing decay or leading to decreased translational efficiency. 3) microRNAs incorporated into an Argonaute complex bind to the 3′ UTR to repress target mRNA expression. 4) RBPs and RNA helicases can either promote or repress mRNA translation. 5) mRNAs and proteins can be segregated in dividing cells to drive their asymmetric inheritance in newborn cells. 6) RNA modifications, such as m⁶A, can affect mRNA stability and mRNA translation. 7) Microexons can change the reading frame or encode premature stop codons to modulate protein expression. These mechanisms may be prevalent in progenitors and neurons.