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Published in final edited form as: Curr Opin Neurobiol. 2020 Oct 23;66:93–102. doi: 10.1016/j.conb.2020.10.001

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

Mariah L Hoye 1, Debra L Silver 1,2,3,4
PMCID: PMC8058166  NIHMSID: NIHMS1642204  PMID: 33130411

Abstract

Regulation of stem cell fate decisions is elemental to faithful development, homeostasis, and organismal fitness. Emerging data demonstrates 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- 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.

Graphical abstract:

Multipotent radial glial cells (RGCs, orange) are transcriptionally primed to enable rapid generation of diverse progeny. Post-transcriptional regulation, including translation, can refine gene expression to specify cell fates.

graphic file with name nihms-1642204-f0001.jpg

Introduction:

Stem cells are self-renewing progenitors whose potency enables generation of diverse cell types. Totipotent embryonic stem cells can produce all germ cell layers. Pluripotent and multipotent stem cells are fate restricted and generate cells of a specific lineage during development or adult homeostasis. For example, in the developing neocortex, pluripotent neural stem cells, termed radial glial progenitor cells (RGCs), generate a diversity of excitatory neurons and glia. Stem cells often reside within a niche, which provides extrinsic cues (either physical or chemical) to influence whether progenitors self-renew or differentiate.

Lineage specification of stem cells is characterized by distinct transcriptional pathways. Yet, across broad cell types including stem cells [1], transcript and protein levels do not always correlate [2,3]. This disconnect between mRNA and protein expression is likely explained by dynamic post-transcriptional regulation. Indeed, gene expression programs rely heavily upon alternative splicing, RNA decay, subcellular RNA localization, and translation [4]. These can be mediated by both cis mechanisms (RNA sequence, secondary structure, epitranscriptomic modifications) as well as trans regulatory factors (RNA binding proteins, termed RBPs, and noncoding RNAs).

Post-transcriptional regulation is widely used in the developing nervous system to sculpt and wire the brain. In this review, we describe emerging evidence that neural progenitors are transcriptionally primed and that cell fates are specified by subsequent post-transcriptional regulation, especially translation. Please also see these in-depth reviews of additional post-transcriptional mechanisms of neocortical development [4–6]. Highlighting the importance of translational control, we discuss mutations in translational machinery which cause neurodevelopmental disorders, including intellectual disability and autism spectrum disorder.

Transcriptional priming is an important mechanism of cortical development

The cerebral cortex is responsible for higher-order cognitive function. It is organized tangentially into functional areas and radially into six laminar layers, which are composed of pyramidal neurons with unique morphologies, axonal targets and molecular profiles [7]. Excitatory neurons are derived from neural progenitors during embryonic neurogenesis (Figure 1). Initially, neuroepithelial cells divide symmetrically in the ventricular zone (VZ) to expand the progenitor pool. These cells differentiate into RGCs, which divide in the VZ to produce either neurons or intermediate progenitors (IPs). RGCs can divide symmetrically to self-renew or asymmetrically to produce either two progenitors (RGC and IP) or a progenitor (RGC or IP) and neuron. In the sub-ventricular zone (SVZ), IPs undergo 1–2 self-renewing divisions before terminally differentiating into neurons [8]. Relative to mice, the composition of progenitors in primates is more complex, where the main neuron producing cells are outer radial glia (also called basal radial glia) [8]. In both mice and humans, excitatory neurons are produced sequentially, with deep layer cortico-thalamic and sub-cerebral projection neurons mainly produced first followed by superficial callosal projections neurons [9]. Following their genesis, newborn excitatory neurons migrate into the cortical plate (CP) using the RGC basal process as a scaffold.

Figure 1. Corticogenesis in mice.

Figure 1.

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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.

A long-standing question in the cortical development field regards the potency of neural progenitors- how do they generate diverse neuronal subtypes and does potency change over the course of development? Early studies suggested that as development proceeds, neural progenitors, which are initially multipotent, become fate restricted [10]. This idea was somewhat challenged by findings that fate-restricted progenitors (which generate superficial neurons) are present at the onset of neurogenesis [11]. Yet, numerous studies have also shown that over the course of development, RGCs retain multipotency and are not restricted to a particular laminar fate [12–15]. Retroviral lineage analysis and Mosaic Analysis Double Markers (MADM) are two orthogonal approaches which enable lineage tracing of progenitor cells. A recent study employing these techniques [16] supports earlier work showing clonal RGCs can stochastically produce neurons with different laminar fates [15], and that a subset of progenitors are lineage restricted [10]. The question of heterochronic progenitor potency was further evaluated by Oberst et al, who isochronically labeled and transplanted E15.5 RGCs into E12.5 cortices [17]. In this younger environment, the older RGCs, which normally produce superficial layer neurons, generated deep layer neurons. Conversely, transplanted IPs lacked this plasticity. In line with this, new single-cell transcriptome data demonstrate that RGCs exhibit a core transcriptional landscape that becomes further refined by cell extrinsic factors as neurogenesis progresses [18]. These data suggest RGCs maintain multipotency, and further, that their potency is influenced by cues from the local environment. However, the possibility remains that there are sub-populations of RGCs and/or IPs that are fate-restricted to produce specific neurons.

A model of transcriptional priming in cortical progenitors

How is multipotency conferred? A body of evidence indicates that neural progenitors express transcripts which encode functions important for both stem cell and neuronal fates [18–20]. From single cell sequencing data, neuronal markers, such as Cux1 and Tle4 mRNA, are expressed in early apical progenitors (presumed RGCs) [18]. Similarly, Ctip2 and Neurod2 mRNAs are readily detectable in newborn IPs [18]. This reinforces microarray studies which show that RGCs express Ngn2 and Tuj1 transcripts, yet the proteins are only expressed at appreciable levels in IPs and neurons, respectively. Notably, in newly generated progeny, Ngn2 and Tbr2 protein are detectable within several hours of their birth [21], and Tuj1 protein is detectable within minutes [22]. Further, some pro-neurogenic proteins, including Neurod2, can also be produced within neural progenitors [23], which when coupled with cell cycle exit, promotes differentiation. Altogether, this suggests there must be mechanisms in place to ensure pro-neurogenic proteins are only produced in cells that are destined to become neurons while pro-proliferative proteins are limited to progenitors.

These transcriptomic insights support a model whereby neural progenitors are transcriptionally primed to generate multipotent fates (Figure 2) [24]. This allows progenitors to express a broad profile of mRNAs important for both pluripotency and differentiation. Post-transcriptional control of both progenitors and newborn progeny enables rapid expression of the proper proteins. In a newly generated neuron, inherited “stem cell” mRNAs may undergo rapid decay and/or translational repression, whereas in stem cells, translational repression would ensure that “neurogenic” RNAs, such as Tuj1 and Neurod2, are not prematurely made into protein. Transcriptional priming is logical from a kinetic standpoint, as transcription can persist over 10 minutes, whereas post-transcriptional regulation is faster, with an average translation rate of about 1 minute [25]. In this regard, RGCs and IPs may rapidly integrate external cues into molecular information required for cell fate specification.

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

Figure 2.

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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.

It is interesting to consider how transcriptional priming mechanisms differ between pluripotent RGCs and fate-restricted IPs, as well as diverse progenitors of primates. In the mouse, IPs primarily undergo terminal neurogenic divisions, and thus their need for transcriptional priming may be lower. In contrast, basal progenitors in humans and non-human primate brains undergo more self-renewing divisions [26,27]. Human organoids, mouse lines and viral tracing that allow lineage mapping to interrogate the fate of proliferative and neurogenic progenitors will be valuable for tackling these questions [28,29]. Pairing these tools with transcriptomic and proteomic analyses will be invaluable towards evaluating how widespread transcriptional priming is across distinct cortical progenitors.

Subcellular mRNA segregation in neural progenitors

A classic model whereby transcriptionally priming promotes cell fates is asymmetric RNA segregation during cell division. In Drosophila, specific mRNAs associate with the apical side of dividing progenitors, and their inheritance is both necessary and sufficient for neurogenic fates [30]. In this context, localization of the pro-neurogenic Miranda transcript relies upon the RBP Staufen2 [31]. Likewise, in asymmetrically dividing RGCs, Staufen2 drives asymmetric inheritance of IP-associated mRNAs, including Prox1 and Bbs2 [32,33]. In contrast to Drosophila, our knowledge of asymmetric RNAs within mitotic cortical progenitors is limited to just a handful of examples.

In contrast, recent studies reveal mRNAs which can asymmetrically localize along the length of a polarized interphase RGC [34,35]. Indeed, over 100 mRNAs associate with Fragile-X associated, FMRP, in basal endfeet structures of RGCs where they can be locally translated [34]. Many RBPs, including FMRP, form ribonucleoprotein (RNP) granules and associate with motor proteins to drive active transport of mRNAs, as seen in neurons [36]. mRNAs within RNP granules are hypothesized to be translationally repressed until they reach their final destination, where their translation can be regulated in an activity-dependent manner [37]. In neurons, localized transcripts have been implicated in outgrowth and synaptic signaling. Strikingly less is known about the function of RNA localization in RGCs; although they are postulated to play roles in cell fate determination, signaling, and the cytoskeleton [35,38]. It will be interesting to determine if mRNAs also subcellularly localize at apical endfeet, whose contact with the CSF may influence RGC fate decisions [39].

Translational regulation of neural progenitor fate

Cis and Trans-factors fine-tune and control translation

Translational control within progenitors and newborn neurons is uniquely suited to rapidly and specifically regulate gene expression (Figure 3). Translation is on average 10X faster than transcription [25], and thus presents a rapid means to shape individual protein expression within newborn cells, either by activating or repressing protein synthesis. Unlike transcription machinery, ribosomes can be positioned subcellularly to translate specific mRNAs in response to local external cues [40,41]. In addition, ribosomal levels and translational output can influence embryonic and mesodermal stem cell fates [42–44], and emerging evidence indicate these mechanisms are central to neocortical development. For example, in neuroepithelial cells ribosome biogenesis rates are initially high but decrease as cells transition to RGCs, and inhibition of ribosomal biogenesis via Myc signaling induces progenitor proliferation [45]. Moreover, specific RBPs may help specify which ribosomal proteins are expressed during cortical development in order to coordinate translation of functionally related mRNAs [46]. Additionally, ribosome heterogeneity, denoted by ribosomal subunit expression, post-translational modifications and rRNA variants can specialize translation machinery across cells [47]. While the function of ribosomal diversity for cortical progenitors is unknown, it is tantalizing to consider how ribosome composition in different progenitors or across progenitor states influences translation and cell fate.

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

Figure 3.

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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.

Similar to the observation of heterogenous ribosomes in distinct cell types, the repertoire of tRNAs is also different in proliferating and differentiated cells in vitro [48]. This tRNA cellular composition is paralleled by expression of mRNAs with specific codons in proliferating versus differentiated cell types [48]. Thus, tRNA abundance and composition can dictate both global translation levels, as well as translation of specific mRNAs. tRNA function, fidelity and stability also rely on specific post-transcriptional modifications to the tRNA. For example, in yeast, loss of tRNA modification at the wobble position of the anti-codon increases ribosome pausing and decreases translation rates [49]. Elucidating the repertoire of tRNAs and their modifications in the developing cortex will be of critical importance, as mutations in tRNA-regulating enzymes are implicated in neurodevelopmental disorders [50]. While tRNAs are notoriously hard to sequence because of their size, structure, and extent of modifications, new advances suggest this analysis is increasingly feasible [50].

RBPs are critical to repress or promote mRNA translation in progenitors, with most prominent examples shown in RGCs. Zahr et al showed that RGCs are transcriptionally primed with mRNAs, such as Brn1 and Tle4, which specify both superficial and deep layer neurons [20]. Notably, both types of transcripts are translationally repressed in RGCs by an RBP complex composed of Pumillo and 4E-T. Depletion of this complex aberrantly specifies neuronal fate, highlighting a role for priming and translational repression in neuronal cell fate. It will be interesting to understand how this repressive complex is controlled by extrinsic and intrinsic signals to differentially specify deep layer and superficial neurons, and further how translational repression influences IPs.

Precise translational control may be achieved by RBPs acting in concert with other trans-acting factors. For example, in RGCs, eIF4E1 can either promote or inhibit translation of neurogenic factors depending upon its association with 4E-T and other RBPs [51,52]. Likewise, during corticogenesis, the Celf1 RBP mediates translational regulation of distinct isoforms of another RBP, Elavl4 [53]. Some RBPs, such as FMRP, may dually function as both translational activators and repressors to influence neurogenesis, depending upon the species [54,55]. Ongoing study of how RBPs control translation will be important for understanding distinct cell fate programs during corticogenesis.

Beyond RBPs, mRNA translation is also fine-tuned by noncoding RNAs, such as microRNAs (miRNA), which bind to 3′ UTRs to repress translation [56]. Many miRNAs control neurogenesis, as recently reviewed [4,6]. Interestingly, the developing neocortex uses opposing gradients of miRNA expression to generate distinct neuronal sub-types [57]. Because miRNAs typically only bind target mRNAs with 7–8 nucleotides of complementarity, they can regulate hundreds of transcripts and shape cellular expression profiles in a concerted manner [58]. Moreover, circular non-coding RNAs, many of which show brain-specific and developmentally regulated expression [59,60], can act as sponges for miRNAs to further refine gene regulation. An important future question is how miRNAs, circular RNAs, and RBPs coordinate in functional networks to control transcriptomes of cortical progenitors and neurons.

The sequence and/or structure of an mRNA can dictate translational control and stem cell fate decisions. A prominent example is the motif-driven mRNA localization of Ccnd2 mRNA, which localizes to basal structures of RGCs via a defined 3′ UTR sequence [35]. Upstream open reading frames (uORFs), which can repress overall translation by either stalling of the pre-initiation complex at a downstream ORF or reducing translational efficiency, are another emerging example of cis-translational regulation [61,62]. uORFs are abundant in eukaryotes and highly conserved in their repressive function. While uORFs have not yet been functionally investigated in cortical progenitors, many uORF-containing transcripts, including Sox2, are important for neurogenesis [62]. Finally, translational output may be influenced by alternative splicing patterns directed by cis- and trans- elements. Notably, recent studies show microexons are frequent in the brain [63,64], and can modulate translation by introducing premature stop codons [65].

Integrating translation and stability

Cell specific transcript decay is another key mechanism to fine tune transcriptional priming. mRNA decay is generally initiated by the removal of the polyA tail, which recruits decapping machinery to the 5′ cap and leads to mRNA degradation. Proper neurogenesis relies upon mRNA decay factors, including those which target transcripts containing nonsense codons [4,66]. Further, several mRNA decay factors are mutated in neurodevelopmental disorders [67]. mRNA decay can also be controlled by RBPs which bind to A+U Rich Elements (AREs) in the 3′ UTR to either promote or inhibit mRNA degradation. HuR is an ARE binding protein with established roles in cortical lamination [46] including through stabilization of the actin regulator Profilin 1 mRNA [68]. Notably, mRNA decay, including nonsense-mediated decay, is intimately connected with translation [69]. For instance, miRNA-mediated translational repression is often coupled to subsequent mRNA decay. Likewise, translation of uORFs can trigger nonsense-mediated decay [62]. Codon optimality also influences translation rates and mRNAs bearing non-optimal codons are often targeted for degradation. For instance, in FMRP knockout neurons, codon optimality influences translational output likely due to mRNA decay [70]. Altogether this suggests mRNA decay is likely to be important for cortical progenitor fates. Importantly, RNA sequencing reflects steady-state transcriptomes, but not the extent of mRNA stability changes. This regulatory layer has not been examined in cortical development.

RNA chemical modifications, dubbed epitranscriptomics, are an emerging layer of translational and stability regulation in stem cells. Amongst over 100 RNA modifications described, N6-methyladenosine (m6A) is the most abundant and is brain-enriched [71]. In cortical RGCs, m6A tagging influences stability of primed transcripts related to neurogenesis, and controls neuronal differentiation [19,72,73]. Consistent with a role in protein synthesis, m6A controls translation locally in axons [74], during axon guidance [75] and in adult neural stem cells [76]. An important research direction will be to understand how epitranscriptomic modifications are integrated with translation and stability factors in RGCs to specify cortical fates.

Translational dysregulation in Neurodevelopmental disorders

The importance of translational regulation in neurogenesis is supported by accumulating evidence linking human mutations in translational regulators to neurodevelopmental disorders. Mutations in ribosomal proteins, initiation and elongation machinery, tRNA-modifying enzymes, and RBPs that regulate translation cause varying degrees of neurological impairment, including intellectual disability (ID), autism spectrum disorder (ASD), microcephaly and epilepsy [77,78].

Many core translation factors serve specialized functions in the nervous system and, when mutated, cause ID and ASD [79,80]. For example, EIF4E, a core translation initiation factor that is mutated in ASD, controls translation of cell cycle- and neurogenesis- associated mRNAs [81]. In RGCs, eIF4E functions are influenced by other RBPs [51,52], and consistent with this, mutations in eIF4E interactors disrupt translation and cause ASD-like behavioral and circuitry deficits in mice [65,82]. Thus, due to their unique regulation in the nervous system, dysregulation of core translation factors, as well as their protein partners, can disrupt neurodevelopment. The extent to which these pathologies are due to impaired translation and cell fate specification remains to be determined.

ATP-dependent RNA helicases can also modulate translation and are implicated in both ID and ASD [83–85]. For example, mutations in the RNA helicase, DDX3X, perturb neurogenesis and impair translation of specific mRNA targets [84]. DDX3X can bind to highly structured 5′ UTRs to promote mRNA translation initiation and translation of uORFs [86]. Notably, ID/ASD linked mutations in three RNA helicases, DHX30, DDX6, and DDX3X, all lead to formation of aberrant RNP granules [83–85]. Such granules have historically been associated with neurodegenerative diseases, but given the wealth of RNA helicases expressed during cortical development [87], these studies suggest aberrant RNP granules may likewise contribute to neurodevelopmental pathologies.

Mutations in tRNA-regulating enzymes are also linked to neurological disorders, suggesting the brain may have specific requirements for this machinery. For example, a tRNA-modifying enzyme, NSUN2, is mutated in ID and microcephaly [88] and loss of NSUN2 decreases global protein synthesis. This may be due to neurogenesis defects as Nsun2 knockout in mice increases IPs and reduces upper-layer neurons [89]. Likewise, mutations in the Cysteinyl-tRNA synthetase which cause microcephaly and developmental delay are associated with altered tRNA charging (and likely translation) [90]. Recently, mutations in Asparaginyl-tRNA synthetase1 (NARS1) were shown to cause microcephaly. NARS1 mutations led to decreased protein synthesis and impaired RGC proliferation in human cortical brain organoids [91]. While these studies highlight pathogenic mutations in tRNA-regulating enzymes, their specific targets in the developing cerebral cortex are unknown.

Conclusions/Summary

While our understanding of neurogenesis has significantly increased with transcriptome analyses, ultimately, many of the mechanisms that govern neural progenitor fate decisions may also be driven post-transcriptionally. The interplay between post-transcriptional mechanisms, involving both cis and trans information, may be coordinated broadly in the form of “RNA regulons” [92]. In cortical progenitors, converging post-transcriptional mechanisms may act in concert to regulate related groups of mRNAs and ultimately, drive different cellular processes, such as cell cycle progression [92]. By considering both the transcriptional and the post-transcriptional landscape at play in cortical progenitors, researchers can formulate a holistic view of cortical development. Moreover, many nodes of RNA regulons are mutated in neurodevelopmental disorders. Thus, studying these diseases will also inform previously unappreciated regulatory processes that drive corticogenesis.

Highlights:

  • Neural progenitors are transcriptionally primed to generate diverse cortical cell types

  • Post-transcriptional control of progenitors and neurons fine tunes cell fate decisions

  • Pro-proliferative and pro-neurogenic mRNAs are translationally controlled by cis- and trans-factors

  • Translation machinery is frequently dysregulated in neurodevelopmental disorders

Acknowledgements

We thank members of the Silver lab for careful reading of this manuscript and LJ Pilaz and Ashley Lennox for use of some modified cartoon images in figures. This work was supported by the Holland-Trice Foundation, the NIH (R01NS083897, R21MH119813, and R01NS110388 to D.L.S.; F32NS112566 to M.L.H), and the Regeneration Next Initiative Postdoctoral Fellowship to M.L.H.

Footnotes

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Conflict of Interest

The authors declare no conflict of interest.

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*paper of special interest

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