Protein Synthesis and Translational Control in Neural Stem Cell Development and Neurogenesis
Abstract and Keywords
Neural stem/progenitor cells (NSCs) are the origin of almost all neural cells in the mammalian brain and generate neurons throughout life. The balance of NSC maintenance and differentiation is thus critical for brain development and function. This balance is precisely controlled by sophisticated gene expression programs at multiple levels. While transcriptional regulation is vital for many aspects of neurogenesis from NSCs, recent studies highlight that protein synthesis controlled by spatiotemporal translational programs plays an equally important role in NSC lineage progression and fate decision. Alterations in coordinated translational programs underlie the pathogenesis of some human diseases. In this review, we discuss how protein synthesis changes in NSCs during neurogenesis, how it is regulated in a global or gene-specific manner by the orchestrated action of the translational machinery and RNA-binding proteins, and how deregulation of protein synthesis in NSCs contributes to neurodevelopmental disorders.
The mammalian central nervous system originates from embryonic neural stem/progenitor cells (NSCs) that are capable of self-renewal or differentiation into all major neural lineages (neurons and glia; Taverna, Gotz, & Huttner, 2014). The earliest population of NSCs consists of neuroepithelial cells (NECs) surrounding the ventricle of the neural tube, which elongate radially to the pial surface. These highly proliferative cells divide symmetrically to make identical daughter stem cells, thereby expanding the pool of NSCs. At the onset of neurogenesis, NECs transform into radial glial cells (RGCs). This transition is accompanied by the switch of NSC division mode from symmetric, proliferative to asymmetric, self-renewing (Delaunay et al., 2017). In this latter mode of division, one RGC gives rise to a daughter RGC, maintaining the stem cell pool, and producing a more differentiated cell, such as a neuron (direct neurogenesis) or a fate-restricted intermediate progenitor cell (IPC) that undergo transient proliferation to make multiple neurons (indirect neurogenesis). After neurogenesis has ceased, NSCs continue to make other cell types (e.g., astrocytes and oligodendrocytes; Taverna, Gotz, & Huttner, 2014). A few NSCs persist into adulthood, becoming adult NSCs capable of generating neurons throughout life (Bond, Ming, & Song, 2015).
Neurogenic differentiation and lineage transition of NSCs is accompanied by dynamic, rapid and coordinated changes in gene expression (Albert & Huttner, 2018, Lennox, Mao, & Silver, 2018). Most research has focused on transcriptional control of fate determinants in NSCs (Albert & Huttner, 2018, Lennox, Mao, & Silver, 2018). However, it has become increasingly apparent that the transcriptome profile of many cell types does not always correlate with the proteome, and gene-specific correlations vary significantly among different cell types at different times (Liu, Beyer, & Aebersold, 2016; Ghazalpour et al., 2011; Edfors et al., 2016; Haider & Pal, 2013). The discordance between mRNA and protein levels is particularly evident in cells and tissues that are engaged in growth and differentiation processes, such as embryonic stem cells (Corsini et al., 2018; Bulut-Karslioglu et al., 2018) as well as the developing mouse limb bud (Fujii et al., 2017). Similarly, NSCs in the developing mouse cerebral cortex have been found to robustly transcribe many proneural genes that promote differentiation, despite the absence of corresponding proteins (Yang et al., 2014). While proteostasis is controlled by both the production and degradation of proteins (Tuoc & Stoykova, 2010), the rate of protein synthesis is found to play a predominant role in determining cell differentiation (Kristensen, Gsponer, & Foster, 2013).
Protein synthesis is most commonly regulated at the step of mRNA translation (Larsson, Tian, & Sonenberg, 2013). At the global level, translation determines the dynamics of the proteome (Sonenberg & Hinnebusch, 2009). At the individual gene level, it fine-tunes protein production using target-specific mechanisms, which frequently involve cis-regulatory elements present in mRNA and trans-acting factors such as RNA-binding proteins (RBPs; Shi & Barna, 2015, Gebauer, Preiss, & Hentze, 2012). In this review, we will discuss the dynamics of protein synthesis in NSCs during neurogenesis and the regulatory mechanisms at both global and gene-specific levels. Examples of RBPs (Pilaz & Silver, 2015: Popovitchenko & Rasin, 2017), microRNAs (Lennox, Mao, & Silver, 2018) and long non-coding RNAs (Quan, Zheng, & Qing, 2017; Aprea & Calegari, 2015) involved in brain development and NSC activation (Baser, Skabkin, & Martin-Villalba, 2017) have been discussed in excellent recent reviews. Here, we will discuss the latest findings on protein synthesis in NSCs and its translational regulation, highlighting examples to illustrate the close relationship between protein synthesis and NSC development and neurogenesis.
Global Protein Synthesis in NSCs
The synthesis of proteins from mRNA is a fundamental process in all living cells. Rather than just a housekeeping function as is often assumed, studies from multiple stem cell systems indicate that changes in overall protein synthesis rates play a specific role in stem cell fate decision (Buszczak, Signer, & Morrison, 2014). For example, in the hematopoietic system, slow-dividing stem cells synthesized fewer proteins than their more differentiated but fast-dividing progenitors (Signer et al., 2014). Although cells that undergo active cell division generally demand more proteins and thus synthesize proteins more rapidly, it was found that when slow-dividing hematopoietic stem cells were induced to divide, they still maintained a lower rate of protein synthesis (Signer et al., 2014). This suggests that low protein synthesis rates in hematopoietic stem cells are not a nonspecific consequence that reflects merely the cell cycle and proliferation status, but rather a stem cell fate determinant. Indeed, a modest decrease or increase of global protein synthesis in hematopoietic stem cells perturbed their fate decision between self-renewal and differentiation (Signer et al., 2014). Similar observations have been made in quiescent skin and muscle stem cells where they displayed low protein synthesis rates independent of the proliferation status, which was required for stem cell maintenance (Blanco et al., 2016; Zismanov et al., 2016). Therefore, low protein synthesis appears to represent a hallmark trait of adult somatic stem cells and is essential for their overall homeostasis.
Low Protein Synthesis Rates as a Hallmark of Adult NSCs
Somatic NSCs in the adult brain are also largely quiescent (Bond, Ming, & Song, 2015). During neurogenesis, quiescent adult NSCs undergo an activation step and re-enter the cell cycle to generate fast-dividing IPCs, which in turn give rise to neuroblasts and neurons (Bond, Ming, & Song, 2015). Similar to hematopoietic, skin and muscle stem cells, quiescent NSCs were found to have markedly lower rates of protein synthesis compared to activated NSCs as well as more differentiated fast-dividing IPCs (Figure 1; Llorens-Bobadilla et al., 2015; Baser et al., 2019; Hwang et al., 2018). Abnormal increase of protein synthesis in quiescent NSCs by deleting the tumor suppressor gene Pten led to aberrant activation of NSCs and ultimately depleted the adult NSC pool due to premature differentiation (Bonaguidi et al., 2011). These findings are consistent with the idea that overall protein synthesis rates may act in a specific way to determine NSC quiescence and homeostasis.
Changes in Protein Synthesis during NSC Lineage Progression
Quiescent adult NSCs are derived from embryonic NSCs (Bond, Ming, & Song, 2015; Taverna, Gotz, & Huttner, 2014). Given that low protein synthesis is an intrinsic property of quiescent adult NSCs, an interesting question arises: Is lowering protein synthesis rates in a subset of embryonic NSCs required and sufficient for their entry into quiescence to become adult NSCs? While a direct comparison between embryonic and adult NSCs is lacking, Chau et al. (2018) showed a drop in protein synthesis rates along the lineage progression of embryonic NSCs. It was found that as the earliest NSCs, NECs had much higher proteins synthesis rates compared to RGCs, which are derived from NECs (Chau et al., 2018). This reduction in protein synthesis in RGCs was unlikely due to their extended cell cycle length and reduced proliferation, since increasing or decreasing the expression of Myc, a master regulator of cell proliferation, did not change global protein synthesis rates in RGCs (Chau et al., 2018). Nonetheless, an aberrant increase of protein synthesis in RGCs through the deletion of Pten led to increased proliferation (Groszer et al., 2001). This suggests that global protein synthesis is not a simple adaptation to the cell cycle status of NSCs but may play a specific role in controlling NSC lineage progression (Figure 1). It will be interesting to determine whether protein synthesis rates further decrease in some or all RGCs over the developmental time and whether this reduction contributes to the establishment of adult NSCs.
Translational Control of Global Protein Synthesis in Neurogenesis
Dynamic changes in protein synthesis during NSC activation are accompanied by changes in the major components of the translational machinery, such as translation initiation factors and ribosomal proteins. For example, upon the differentiation of NSCs to neurons, enhanced protein synthesis was correlated with an increase in the transcriptional upregulation of ribosomal subunits and in the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E; Shin et al., 2015; Chau et al., 2018; Hwang et al., 2018), which synergistically promote global translation. This suggests that the regulation of protein synthesis at the step of translation may play a significant role in NSC maintenance and differentiation.
Cap-Dependent Translation, Initiation Factors and mTORC1
Most mammalian mRNA undergoes cap-dependent translation (Sonenberg & Hinnebusch, 2009). As the rate-limiting factor, eIF4E controls translational initiation by binding to the 5′cap of mRNA and interacts with eIF4G to recruit the translational machinery (Sonenberg & Hinnebusch, 2009; Jackson, Hellen, & Pestova, 2010). eIF4E can be sequestered from eIF4G by eIF4E-binding proteins (4E-BPs), thus preventing translation (Jackson, Hellen, & Pestova, 2010). In adult NSCs, Hartman et al. (2013) linked cap-dependent translation to NSC homeostasis by showing that the loss of 4E-BP enhanced NSC differentiation into neurons, and conversely, expressing a mutant form of 4E-BP that constantly bound to eIF4E to block cap-dependent translation promoted NSC self-renewal at the expense of differentiation. A critical upstream regulator of 4E-BPs and the cap-dependent translation is mechanistic target of rapamycin complex 1 (mTORC1), a central signaling hub that coordinates protein synthesis and cell growth (Meng, Frank, & Jewell, 2018). Activated mTORC1 phosphorylates 4E-BPs, releasing them from eIF4E and thus enhances global translation (Meng, Frank, & Jewell 2018). In quiescent NSCs, mTORC1 activity was found to be maintained at low levels, corresponding to their low protein synthesis rates (Paliouras et al., 2012). In contrast, more differentiated transient-amplifying IPCs possessed higher mTORC1 activity, consistent with the observation that NSC differentiation was accompanied by an upregulation of protein synthesis (Llorens-Bobadilla et al., 2015; Baser et al., 2019; Blair et al., 2017). Forced activation of mTORC1 depleted NSCs in the adult mouse brain due to aberrant differentiation (Hartman et al., 2013; Bonaguidi et al., 2011), whereas mTORC1 inactivation caused a lengthening of the NSC cell cycle and induced a quiescence-like phenotype, leading to impaired neurogenesis and microcephaly (Han et al., 2008; Paliouras et al., 2012; Cloëtta et al., 2013). Thus, the regulation of cap-dependent translation through the mTORC1-eIF4E pathway is essential for the balance of NSC maintenance and differentiation.
Another well-known regulator of global protein synthesis and stem cell homeostasis is eIF2, an initiation factor that brings methionyl-tRNAi (Met-tRNAi) to ribosomes to initiate translation (Jackson, Hellen, & Pestova, 2010). Phosphorylation of the eIF2 α-subunit prevents reloading Met-tRNAi and attenuates translational initiation (Jackson, Hellen, & Pestova, 2010). In muscle stem cells, hyperphosphorylation of eIF2α maintained global protein synthesis at low levels to preserve stem cell quiescence (Zismanov et al., 2016). Interestingly, eIF2α was also found to be hyperphosphorylated in NSCs, correlating with low protein synthesis rates (Hwang et al., 2018). Upon induction of neurogenic differentiation, a decrease of eIF2α phosphorylation was observed, accompanying an increase in protein synthesis (Hwang et al., 2018). Nonetheless, it has yet to be determined whether eIF2α mediates the translational changes in NSCs and contributes to neurogenesis.
Transfer RNA and RNA Modifications
Like other RNA species, tRNA molecules undergo various post-transcriptional modifications that contribute to the regulation of global protein synthesis (Roundtree et al., 2017; Pan, 2018). Loss of appropriate modifications can cause tRNA degradation, resulting in reduced translational accuracy and protein synthesis (Pan, 2018; Roundtree et al., 2017). For example, some cytoplasmic tRNAs bare a 5-methoxycarbonylmethyl (mcm5) or 5-carbamoylmethyl (ncm5) modification at the wobble uridine site (U34), loss of which weakens the efficiency and fidelity of translation (Tuorto & Lyko, 2016). The mcm5 and ncm5 modifications are catalyzed by the Elongator (Elp) complex (Tuorto & Lyko, 2016). Laguesse et al. (2015) showed that deletion of the catalytic subunit (Elp3) of the Elp complex in mice elicited codon-specific translational pausing, which impaired NSC differentiation and ultimately led to microcephaly. Codon-specific translation defects can trigger protein aggregation (Nedialkova & Leidel, 2015). In Elp3 deleted NSCs, misfolded proteins were found to accumulate in the ER and induced unfolded protein response (UPR; Laguesse et al., 2015). It was thus proposed that upregulated UPR may account for neurogenesis defects after Elp3 deletion (Laguesse et al., 2015). While the specific mechanisms that mediate the effect of UPR on NSCs are still not fully understood, it likely involves eIF2α. It was found that Elp3 deletion led to increased phosphorylation of eIF2α (Laguesse et al., 2015), consistent with the fact that a main transducer of UPR is protein kinase RNA (PKR)-like ER kinase (PERK) that phosphorylates eIF2α to attenuate global protein synthesis and relieve the ER stress (Pavitt & Ron, 2012).
Cytosine-5 methylation (m5C) is also essential for tRNA maturation; loss of m5C modification causes increased cleavage and fragmentation of tRNA (Pan, 2018; Tuorto et al., 2012). The vast majority of tRNAs are methylated by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), of which deletion was shown to downregulate global protein synthesis in the developing mouse brain (Tuorto et al., 2012, Tuorto & Lyko, 2016; Blanco et al., 2014). The loss of NSUN2 perturbed neurogenesis and led to microcephaly (Blanco et al., 2014, Flores et al., 2017). Despite a similar reduction in protein synthesis to that seen in the mcm5 and ncm5 deficiency, perturbations in tRNA m5C modification resulted in an accumulation of IPCs that failed to differentiate into neurons, rather than a depletion of IPCs (Flores et al., 2017; Laguesse et al., 2015). The opposing effects of tRNA processing defects induced by Elp3 and NSUN2 deletions may be due to additional targets of Elp3 and/or NSUN2 since RNA modification enzymes frequently display substrate promiscuity (Roundtree et al., 2017). Indeed, NSUN2 is known to methylate both mRNA and long non-coding RNA (Roundtree et al., 2017, Hussain et al., 2013, Khoddami & Cairns, 2013, Yang et al. 2017). In this regard, methylation of mRNA at the N6 position of adenosine (m6A) was shown to regulate NSC self-renewal and neurogenic differentiation (Wang et al., 2018; Yoon et al. 2017).
Ribosomes are the center of the whole protein synthesis machinery and key for fine-tuning the proteome. While the biogenesis of ribosomes has been linked to stem cell homeostasis in other systems (Sanchez et al., 2016; Khajuria et al., 2018), it remains inconclusive as to whether and to what extent ribosome biogenesis affects NSC development in the mammalian brain. For example, a reduced transcription of ribosomal RNA and ribosomal protein genes (e.g., Rpl11 and Rps12, two factors crucial for ribosomal assembly) was associated with NSC lineage progression in the embryonic cortex (transition from NECs to RGCs), although cytoplasmic ribosome density in NSCs was found to be unchanged (Chau et al., 2018). Similarly, the activation of quiescent adult NSCs was correlated with an initial upregulation of ribosomal genes before cell cycle entry (Dulken et al., 2017; Llorens-Bobadilla et al., 2015; Shin et al., 2015). However, when NSCs were forced to proliferate, protein synthesis rates were not affected despite an enhancement in the transcription of ribosomal protein genes (Chau et al., 2018), suggesting additional levels of regulation. Indeed, it was recently found that in proliferative NSCs, the expression of many ribosomal protein genes was themselves coordinated at the translational level according to NSC developmental states (Blair et al., 2017). Therefore, the role of ribosome biogenesis in NSC development and neurogenesis is likely to be more complex and involve multiple regulatory mechanisms.
One such mechanism includes the changes in the composition of ribosomes. Often assumed to be an invariant, homogeneous set of molecular machinery, recent evidence shows that ribosomes are heterogeneous regarding their molecular composition (Shi & Barna, 2015; Guo, 2018). They are made up of different ribosomal proteins within and across different tissues, allowing the ribosomes to meet the varying needs of protein synthesis in the cell (Slavov et al., 2015, Shi et al., 2017). In the mammalian brain, the protein composition of ribosomes was found to be cell-type specific (e.g., Rpl7l1 in NSCs), showing dynamic changes throughout development and in response to extracellular signals (Kraushar et al., 2015; Kraushar et al., 2016). Further studies will need to determine to what extent and how the spatiotemporal expression of distinct ribosomal components differentially affects protein synthesis, NSC lineage progression and neurogenesis.
Target-Specific Translational Control of Neurogenesis
The translation of mRNA can be regulated at a global level (as discussed in the previous sections), changing the whole proteome, or a transcript-specific level, affecting the synthesis of a single or a subset of proteins to achieve specific cellular functions. An interesting observation in NSCs was that they not only transcribed genes essential for self-renewal (e.g., Hes1, Sox2) but also constantly made mRNA from many genes that induce neuronal differentiation (e.g., NeuroD1, Neurogenin1; Yang et al., 2014; Zahr et al., 2018). Simultaneous transcription of genes that encode proteins with conflicting functions requires gene-specific control at translational and/or post-translational levels to ensure proper neurogenesis. Target-specific translational control provides several advantages in this regard. First, and perhaps the most apparent, it allows rapid production of specific proteins from pre-existing mRNA to elicit immediate actions. This bypasses the need for the transcription, splicing and export of new mRNA. Rapid synthesis of fate determinant proteins may facilitate timely neuronal fate commitment. Second, target-specific translational control can fine-tune gene expression regarding the onset, termination and level of expression of select genes that may have related or conflicting functions. Third, it allows for local production of select proteins to deliver spatial-specific functions by transporting translationally silenced mRNAs to different compartments of NSCs. This is particularly relevant to NSC fate decision, as translationally controlled cell fate determinants can be asymmetrically segregated during NSC self-renewing division (Delaunay et al., 2017). RBPs are essential players that elicit target-specific regulation of mRNAs. Several RBPs involved in NSC homeostasis have been recently reviewed elsewhere (Pilaz & Silver, 2015; Popovitchenko & Rasin, 2017; Lennox, Mao, & Silver, 2018; Baser, Skabkin, & Martin-Villalba, 2017). In the following sections, we will focus on the latest findings and a few classic examples to discuss how NSCs employ spatiotemporal translational regulation to instruct neurogenesis.
RBP-Mediated Translational Activation and Repression in NSCs
Modulating the translation of specific mRNA by RBPs before or after they are needed is a rapid mechanism to control differentiation. The embryonic lethal abnormal vision-like 4 (Elavl4/HuD) is one such RBP that activates translation of selective transcripts to promote neurogenesis. HuD was found to be expressed in NSCs throughout development and into adulthood (Bronicki & Jasmin, 2013). Loss of HuD in mice enhanced NSC self-renewal at the expense of neurogenic differentiation, whereas ectopically expressing HuD promoted neurogenesis and neurite development (DeBoer et al., 2014). Using CRAC (cross-linking and analysis of cDNAs), Tebaldi et al. (2018) recently found that HuD predominantly bound to the 3′ untranslated regions (UTRs) of a select set of mRNAs that encode regulators of protein synthesis, including mTORC1-responsive ribosomal proteins (e.g., Rps20, Rpl32) and translation factors (e.g., Eif4a1, Eef1a1). Several proneural genes (e.g., Ascl4, Msi1) were also HuD targets. Upon HuD overexpression, the translation of these mRNAs was upregulated to enhance neural differentiation (Tebaldi et al., 2018). HuD relied on both the poly-A tail and cap structure of mRNA to enhance translation, suggesting that HuD may work with the translational initiation machinery to promote mRNA translation (Fukao et al., 2009).
In addition to initiating translation, components of the translation initiation machinery can also be recruited for repressing the translation in a target-specific manner. For example, the initiation factor eIF4E can interact with a translational repressor eIF4E-transporter (4E-T) in self-renewing NSCs to selectively target proneural mRNAs (e.g., Neurogenin1 and NeuroD1) to the processing bodies (P-bodies), cytoplasmic foci where mRNA repression and decay occur (Standart & Weil, 2018; Luo, Na, & Slavoff, 2018; Yang et al., 2014). Disruption of the eIF4E/4E-T repressive complex or the P-bodies resulted in abnormal activation of proneural mRNAs, leading to compromised NSC self-renewal and premature neurogenesis (Yang et al., 2014). This suggests that translational repression plays a critical role in maintaining the stem cell state of NSCs. While the 4E-T complex regulates specific mRNA, 4E-T itself cannot directly recognize mRNA (Kamenska et al., 2014; Ozgur et al., 2015), but is likely to corporate with target-specific RBPs for this function (Figure 2). In NSCs, one such RBP is Smaug2, which was shown to interact with 4E-T and repress the translation of Nanos1 mRNA, a proneural factor (Amadei et al., 2015). Knocking down Smaug2 in NSCs caused an aberrant increase of Nanos1 translation, leading to premature neurogenesis and phenocopied 4E-T loss of function (Amadei et al., 2015; Yang et al., 2014). This suggests that 4E-T forms a complex with Smaug2 and likely other RBPs to regulate neurogenesis. A recent interactome study has brought new insights into this by identifying several RBPs that interact with 4E-T in human kidney embryonic cells (Youn et al., 2018). It is thus likely that 4E-T forms various sub-complexes with discrete RBPs to orchestrate distinct groups of functionally related mRNAs (i.e., mRNA regulons) to control different aspects of neurogenesis. Assessing the functional similarities and differences of 4E-T sub-complexes in NSCs would be valuable for understanding how RBP-mediated regulation of mRNA coordinates the diverse aspects of neurogenesis. In this regard, some progress has been recently made revealing the mechanisms by which RBPs regulate the temporal genesis of neurons with distinct identities (see “Translational Control for the Temporal Genesis of Neuronal Subtypes”).
Translational Control for the Temporal Genesis of Neuronal Subtypes
The mammalian neocortex is perhaps one of the best and most-studied parts of the brain with respect to the genesis of different subtypes of neurons, owing to its highly organized structure and the stereotypic pattern of temporal neurogenesis (Taverna, Gotz, & Huttner 2014). Typically, the neocortex is organized into six layers (I–VI), characterized by discrete subtypes of projection neurons that express unique repertoires of genes (Custo Greig et al., 2013). For example, upper-layer (II–IV) neurons express POU class III homeobox 3 (Brn1) and cut-like homeobox 1 (Cux1), whereas deep-layer (V/VI) neurons express Fez family zinc finger protein 2 (Fezf2) or transducing-like enhancer of split 4 (Tle4; Custo Greig et al., 2013). Notably, distinct projection neuron subtypes arise from a common pool of NSCs, but at different developmental time points (Toma & Hanashima, 2015). Lineage tracing and transplantation experiments suggest that at least some NSCs can change their potential to produce multiple neuronal subtypes for both deep and upper cortical layers, a potential that becomes progressively restricted over time (Gao et al., 2014). It is generally thought that NSCs assign the initial identity to neurons by expressing specific subtype genes, such as Tle4 and Brn1 and that a switch in the expression of these genes over the course of development directs a temporal transition from the production of deep-layer to upper-layer neurons (Toma & Hanashima, 2015). Interestingly, Zahr et al. (2018) showed that incompatible subtype identity genes were frequently transcribed together. For example, in earlier-stage NSCs, when deep-layer neurons were being generated, identity genes for later-stage upper-layer neurons, such as Brn1 and Cux1, were transcribed before they were needed. Conversely, at a later developmental stage, when upper-layer neurons were being generated, several identity genes for deep-layer neurons, such as Tle4, were still actively transcribed. Although the transcription of incompatible genes seems paradoxical, a subsequent level of translational control ensures appropriate spatial and temporal protein expression. The authors showed that this translational regulation was partly mediated by an RBP Pumilio2 (Pum2) and its binding partner 4E-T (Zahr et al., 2018). Knockdown of 4E-T or Pum2 in NSCs resulted in misspecification of neuronal subtype identities, a phenotype that was not observed when Smaug2 was perturbed (Zahr et al., 2018, Amadei et al., 2015). This suggests that Pum2 organizes a distinct 4E-T sub-complex in NSCs that prevents promiscuous translation of incompatible identity genes to ensure genesis of neurons with the correct subtype identities (Figure 2).
Another RBP that interacts with the translational machinery to regulate neuronal subtype identity is HuR (Kraushar et al., 2014). Kraushar et al. (2014) showed that HuR deletion in the mouse brain perturbed the assembly of polyribosomes (polysomes), where multiple ribosomes are recruited and active mRNA translation occurs, and compromised ribosome specificity for selective transcripts. This caused aberrant translation of genes specific to layer II, III, and V, leading to an abnormal laminar distribution of deep-layer neurons. Interestingly, the impact of HuR deletion varied in a temporal-dependent manner (Kraushar et al., 2014), suggesting that mRNA regulatory programs coordinated by HuR, and possibly other RBPs, are under dynamic temporal control. It is likely that at different developmental stages, RBPs are organized into discrete complexes with different protein-binding partners and target mRNAs to precisely control NSC lineage progression and neuronal differentiation (Buchan, 2014). The mechanisms that underlie the dynamic assembly of distinct RBP complexes in NSCs are still not well understood.
uORFs and Translational Regulation
Upstream open reading frames (uORFs) are small ORFs that reside upstream of main ORFs, frequently acting as cis-acting repressor elements (Barbosa, Peixeiro, & Romão, 2013; McGeachy & Ingolia, 2016; Johnstone, Bazzini, & Giraldez, 2016). When uORFs are recognized and translated, fewer ribosomes are available for translation of the main ORFs downstream, resulting in translational repression. In other cases, the stop codon of a uORF can be recognized as premature and trigger nonsense-mediated mRNA decay, thus serving as another mean to downregulate translation (Somers, Pöyry, & Willis, 2013). uORF-mediated translational control is a widespread regulatory mechanism for gene expression in mammals (Chew, Pauli, & Schier, 2016; Barbosa, Peixeiro, & Romão, 2013; Johnstone, Bazzini, & Giraldez, 2016). In mouse limb buds and the neural tube, Fujii et al. (2017) showed that genes encoding critical components of core signaling pathways (e.g., Shh, Wnt) were selectively repressed at the level of translation, which was mediated by uORFs. Intriguingly, a recent study by Blair et al. (2017) further showed that uORF might also play a role in controlling translational efficiency during embryonic stem cell differentiation into NSCs. For instance, the translation of an essential NSC gene Sox2 was upregulated upon neural differentiation and was correlated with less ribosome occupancy at its uORF versus the main ORF downstream. Similarly, the distribution of ribosomes in uORFs versus main ORFs changed for a different set of genes upon differentiation of NSCs into neurons (Blair et al., 2017).
The mechanisms that underlie gene-specific uORF regulation in neural stem cell maintenance and neurogenesis remain mostly unknown. Findings from muscle stem cells suggest that phosphorylation of eIF2α may be a critical node of uORF regulation for stem cell maintenance by inducing ribosome bypass of uORFs in the transcripts of stemness genes (Zismanov et al., 2016). It is plausible that similar mechanisms may contribute to uORF regulation in NSC homeostasis. A few RBPs have also been implicated in orchestrating translation of the uORF versus the main ORF. In a recent study, Zhang et al. (2016) showed that the heterogeneous nuclear ribonucleoproteins hnRNPA2B1 and hnRNPA0, as well as Elavl1/HuR bound to and enhanced the translation of the uORFs of target genes to repress the translation of main ORFs. Downregulation of these RBPs increased target protein synthesis (Zhang et al., 2016). Intriguingly, HuR deletion in the developing mouse cortex reduced neurogenic differentiation of NSCs and decreased cortical thickness (García-Domínguez et al., 2011; Kraushar et al., 2014). It was found that HuR regulated neurogenesis by stabilizing the mRNA of Delta-like 1 (Dll1), a ligand for the Notch pathway (García-Domínguez et al., 2011; Kraushar et al., 2014). Nonetheless, HuR can bind to hundreds of mRNAs in a context-specific manner (García-Domínguez et al., 2011; Kraushar et al., 2014; Calaluce et al., 2010). In the future, it would be interesting to assess whether uORF-mediated translational repression of mRNA targets may be a mechanism used by HuR to regulate neurogenesis.
Asymmetric Division and Spatial Control of Translation in NSCs
Another driving force underlying NSC fate decision is the asymmetric segregation of cell fate determinants between two daughter cells (Figure 3). As fate determinants, RBPs and mRNAs have been best-understood in model organisms. For example, the asymmetric localization of translationally repressed Bicoid mRNA and its RBP Staufen in the fly oocytes sets the morphogen gradients essential for the proper spatial patterning of the developing embryo (Ferrandon et al., 1994). Two recent studies showed that similar mechanisms governed asymmetric fate decision of NSCs in the developing mouse brain. It was found that in dividing NSCs, mRNAs encoding proneural factors, such as Prox1, Trim32 and Bbs2, were translationally repressed and preferentially distributed to one daughter cell during asymmetric division (Kusek et al., 2012; Vessey et al., 2012). These proneural mRNAs were shown to be bound and repressed by Staufen2 (Stau2), a human homolog of fly Staufen, which was similarly segregated asymmetrically during cell division (Kusek et al., 2012; Vessey et al., 2012). Knockdown of Stau2 consistently led to symmetric distribution and aberrant translation of Prox1 in daughter cells, resulting in compromised NSC self-renewal and premature neurogenesis (Kusek et al., 2012; Vessey et al., 2012).
The segregation of fate determinants can occur not only in the cell body of NSCs but also other cellular structures, such as the basal process that is extended radially and contacts the basal lamina (Pilaz & Silver, 2017; Kosodo & Huttner, 2009). At the symmetric proliferation stage, the basal process of NSCs is split into two with each inherited by one daughter cell (Kosodo et al., 2008). In contrast, the basal process of self-renewing NSCs at the neurogenic stage is retained by only one daughter cell during mitosis (Miyata et al., 2001; Noctor et al., 2001). It is thus proposed that cell fate determinants stored in the basal process control the fate decision of the daughter cell that retains the process after cell division. Several groups have identified specific mRNAs showing polarized distribution biased to the basal process (Figure 3). For example, the mRNA of Transitin was found to be present along the basal process to the endfeet in chicken NSCs, although the functional significance of this distribution is not well understood (Lee & Cole, 2000). In the mouse cortex, Tsunekawa et al. (2012) showed that the mRNA of Cyclin D2 (Ccnd2), a cell cycle regulator, was mainly localized near the basal lamina throughout development. The inheritance of the basal process was frequently associated with stronger Ccnd2 expression in daughter cells (Tsunekawa et al., 2012; Pilaz et al., 2016). Using loss- and gain-of-function approaches, the authors showed that ectopic expression of Ccnd2 in daughter cells inhibited neuronal differentiation, whereas ablation of Ccnd2 promoted it. This is consistent with the idea that the asymmetrical inheritance of the basal process and the cell fate regulators such as Ccnd2 instructs the maintenance of NSC fate in one daughter cell (Tsunekawa et al., 2012). Nonetheless, it is still not clear whether the fate decision is mediated by the transport of basally synthesized Ccnd2 proteins back to the cell body or by other factors that induce local upregulation of Ccnd2 expression.
Given that the localized translation of Ccnd2 mRNA is a critical control point, it first must be repressed and localized to the cellular region that is asymmetrically distributed. A cis-regulatory element in the 3′UTR of Ccnd2 and a trans-acting RBP, fragile X mental retardation protein (FMRP), were found to mediate the localization of Ccnd2 mRNA to the endfeet (Pilaz et al., 2016). In the absence of FMRP, the basal localization of Ccnd2 mRNA in embryonic NSCs was impaired (Pilaz et al., 2016). However, deletion of Fmr1, the gene that encodes FMRP, caused NSC depletion and premature differentiation in the embryonic cortex, a phenotype opposite to that seen in Ccnd2 overexpression (Tsunekawa et al., 2012, Saffary & Xie, 2011). This suggests that distinct cis- or trans-acting factors may differentially regulate the transport and translation of specific mRNA. In this regard, another RBP, IGF2BP1 (IMP1) can also bind to Ccnd2 mRNA (as well as Ccnd1 mRNA) and regulate their expression (Nishino et al., 2013). While Ccnd2 displayed a biased distribution to the basal process, Ccnd1 mRNA and IMP1 were predominantly located in the cell body of NSCs (Nishino et al., 2013; Tsunekawa et al., 2012). Similarly, IMP1 loss-of-function resulted in compromised NSC self-renewal and aberrant neurogenesis (Nishino et al., 2013). Elucidating the mechanisms that underlie the complex interaction between cis-regulatory elements on mRNAs and discrete RBPs will be important in understanding how translational programs coordinate NSC homeostasis and neurogenesis (Figure 3).
Protein Synthesis and Neurogenesis in Human Neurodevelopmental Disorders
Growing evidence suggests that the dysregulation of protein synthesis represents a shared feature of several complex neurodevelopmental disorders, such as autism spectrum disorder (ASD) and schizophrenia (Louros & Osterweil, 2016; Tahmasebi et al., 2018). This frequently involves mutations that directly or indirectly affect mRNA translation in a global or target-specific manner (Tahmasebi et al., 2018). Given that NSCs are tightly regulated at the translational level, it is not surprising that NSC self-renewal and neurogenesis are often perturbed in these disorders. This perturbation in NSC self-renewal and neurogenesis can cause macroscopic abnormalities of the brain structure, such as focal patches of disorganized neurons that are seen in some ASD patients (Geschwind & Levitt, 2007; Willsey et al., 2013; Stoner et al., 2014; Bailey et al., 1998; Hutsler, Love, & Zhang, 2007).
Dysregulation of Global Protein Synthesis in NSCs
A downregulation of the mTOR pathway and a reduction in the expression of genes involved in protein synthesis have been found in postmortem brain tissues from idiopathic ASD cases (Ginsberg et al., 2012, Nicolini et al., 2015). In contrast, schizophrenia cases showed upregulation of genes involved in mRNA translation (Darby, Yolken, & Sabunciyan, 2016). Similar perturbations in the mTOR signaling pathway were also observed in syndromic ASD and other neurodevelopmental disorders (Troca-Marín, Alves-Sampaio, & Montesinos 2012), such as the fragile X syndrome (FXS; Jacquemont et al., 2018) and tuberous sclerosis complex (TSC; Tsai et al., 2014). While insightful, postmortem analysis at the postnatal stage allows only a static measurement at the endpoint of the disease and cannot provide information on the developmental trajectory that leads to such outcomes. Many ASD susceptibility genes identified in human genetic studies are expressed in the early phases of brain development when NSCs undergo active neurogenesis (Iossifov et al., 2014). This suggests that perturbations in protein synthesis may already show adverse impacts on NSCs and neurogenesis during early brain development, which likely contributes to the pathogenesis of these diseases (Kaushik & Zarbalis, 2016; Packer, 2016).
The use of patient-derived induced pluripotent stem cells (iPSCs) offers a unique opportunity to understand the underlying mechanisms and the developmental trajectory perturbed in neurodevelopmental disorders (Ardhanareeswaran et al., 2017). In a recent study, Boland et al. (2017) generated iPSC-derived NSCs and neurons from several individuals with FXS. They found that patient-derived NSCs showed reduced protein synthesis and delayed early neurogenesis (Boland et al., 2017), a phenotype opposite to that seen in Fmr1 mutant mice (Castrén et al., 2005, Saffary & Xie, 2011). This discrepancy may reflect differences in culturing and experimental conditions. In another study, Topol et al. (2015) generated iPSCs from schizophrenia patients and showed that protein synthesis was upregulated in iPSC-derived NSCs, leading to an increase in total protein levels. This global enhancement of protein synthesis appeared to be a direct result of upregulation in the translational machinery, as both ribosomal proteins and initiation and elongation factors were markedly increased in patient-derived NSCs (Topol et al., 2015). The alterations in protein synthesis were only seen in NSCs; neither iPSCs nor iPSC-derived neurons showed different protein synthesis rates and total protein levels compared to healthy controls (Topol et al., 2015). Intriguingly, cells derived from a nasal biopsy of the olfactory mucosa in schizophrenia patients, in contrast, showed a significant reduction in protein synthesis rates, accompanied by a decrease in ribosomal biogenesis, downregulated mTOR signaling and reduced levels of initiation factors (e.g., eIF2; English et al., 2015). These context-dependent differences in protein synthesis were also observed in a cell model for Rett syndrome, where the causal gene methyl CpG binding protein 2 (MECP2) was deleted in human ESCs (Li et al., 2013). A global reduction of nascent protein synthesis and mTOR signaling was found in ESC-derived neurons but not in ESC-derived NSCs (Li et al., 2013). These findings indicate that disease-related alterations in protein synthesis occur in a manner specific to cell-type and their developmental stage. Given the alterations in global protein synthesis, it will be interesting to assess further if the balance of self-renewal and neurogenesis is affected in patient-derived NSCs.
Perturbation in the Translational Machinery
Human genetic studies of neurodevelopmental disorders have identified mutations in many genes that encode essential components of the translational machinery (Scheper, van der Knaap, & Proud, 2007). In some individuals with microcephaly, intellectual disability and ASD, de novo missense mutations in the ribosomal protein gene RPS23 (uS12) were found to impair polysome formation and the accuracy of mRNA translation (Paolini et al., 2017). Mutations in genes encoding other ribosomal proteins, such as RPL10 (uL16, or AUTSX5) have also been linked to intellectual disability and ASD (Klauck et al., 2006, Brooks et al., 2014). Furthermore, it was found that the copy number of active ribosomal genes was significantly lower in ASD cases, whereas patients with schizophrenia had more ribosomal genes (Porokhovnik et al., 2015, Malinovskaya et al., 2018). Nonetheless, the pathological impact of these changes on NSCs and neurogenesis remains to be determined.
In addition to ribosomal defects, some mutations affect translational initiation. For example, mutations that lead to eIF4E overproduction were found in some ASD patients (Neves-Pereira et al., 2009). Modeling of this eIF4E perturbation in adult mice showed an increase in the translation of several synaptic proteins in neurons, including the ASD-risk factor Neuroligin (Gkogkas et al., 2013; Santini et al., 2013). In line with the aberrant increase of translation, inhibiting cap-dependent initiation reversed ASD-related behavior seen in these mice (Santini et al., 2013; Gkogkas et al., 2013). Intriguingly, in the developing cortex, ectopic expression of eIF4E was found to increase NSC proliferation at the expense of neurogenesis, likely by inducing target-specific translational repression of proneural genes (Yang et al., 2014). This suggests that perturbed translation caused by genetic alterations in eIF4E may have an adverse impact on brain development at multiple stages. Another example of perturbation in translational initiation comes from TSC, a rare genetic disorder characterized by benign tumors (Tsai et al., 2014). TSC is caused by mutations in TSC1 and TSC2 genes, which are upstream negative regulators of mTORC1. Deletion of Tsc1 or Tsc2 in mice led to aberrant activation of mTORC1 and a global increase in protein synthesis in adult NSCs, compromising the quiescent state of NSCs and causing their premature differentiation (Magri et al., 2013; Mahoney et al., 2016).
RBPs in Neurodevelopmental Disorders
Several RBPs have been linked to neurodevelopmental disorders (Sartor et al., 2015). These could represent effects through specific mRNA rather than global changes. These RBPs are either found to be genetically perturbed in human patients such as FMRP (mutated in FXS/ASD) or differentially expressed under pathological conditions to induce a broader impact on mRNA that encode disease risk factors. In a recent study, Parras et al. (2018) showed that cytoplasmic polyadenylation element binding protein 4 (CPEB4) orchestrated mRNAs that encode many high-confidence ASD risk factors (e.g., Dyrk1a, Ptchd1). In a group of idiopathic ASD patients, the expression of CPEB4 was aberrantly regulated; a CPEB4 isoform without exon four was increased with a concomitant decrease of total CPEB4 protein levels (Parras et al., 2018). The altered expression of CPEB4 resulted in a reduction of translational efficiency for its bound mRNAs that are encoded by ASD risk genes, leading to ASD-like changes at the neuroanatomical, electrophysiological and behavioral levels in mouse models (Parras et al., 2018). Given that CPEBs are expressed throughout development (Ivshina, Lasko, & Richter, 2014), it remains unknown whether altered CPEB4 expression affects brain development at earlier stages when neurogenesis occurs. Nonetheless, deletion of Orb2, the fly homolog of human CPEB2-4 isoforms, caused premature neural differentiation of NSCs (Hafer et al., 2011), suggesting a potential role of CPEBs in developing neurogenesis in mammals.
Alteration in cis-Regulatory Elements
In some cases, pathological features arise from mutations in cis-regulatory elements of specific genes that affect their translation. Suhl et al. (2015) identified a variant located in FMR1 3′UTR. This mutation reduced translation of FMR1 mRNA due to its compromised interaction with the trans-acting factor HuR (Suhl et al., 2015). Another example is MECP2, the causal gene for Rett syndrome. Mutations in MECP2 3′UTR caused a reduction in MECP2 translation and may contribute to the clinical expression of pathological phenotypes (McGowan & Pang, 2015). Interestingly, MECP2 mRNA underwent 3′UTR-based stabilization and translational activation during neural differentiation of human ESCs (Rodrigues et al., 2016). This process was controlled by the combinatory actions of trans-acting factors including the RBPs Tia1, HuC, Pum1, and pluripotent-specific miRNAs (Rodrigues et al., 2016). It will be interesting to investigate if and how these ASD-related trans-acting factors, together with CPEB4, act in post-transcriptional networks to coordinate NSC lineage progression and neurogenesis.
Over the past few years, growing evidence indicates that protein synthesis orchestrated by the translational machinery, and RBPs play a critical role in NSC maintenance and differentiation in the mammalian brain. Despite significant recent advances, our understanding of how coordinated translational events regulate NSCs and neurogenesis is far from complete. Several outstanding questions remain unresolved. For example, how do translational programs instruct NSC fate transition to make different neuronal subtypes and glial cells throughout development? Do translational programs contribute to the developmental establishment of adult NSCs? How are discrete mRNA-protein complexes organized and regulated in NSCs to coordinate the translation of functionally related mRNAs to instruct neurogenesis? During asymmetric division in NSCs, what upstream mechanisms trigger the differential activation or repression of fate determinant mRNAs to help daughter cells acquire different cellular fates, and at what cell cycle stage is the fate decision made? How do translational programs integrate niche signals to instruct NSC fate decision? The use and development of new molecular and biochemical techniques will bring novel insights into these questions. For example, genome-wide identification and comparison of 4E-T-interacting RBPs in NSCs and other cell types will help elucidate functional similarities and differences of discrete translational repression 4E-T sub-complexes and their roles in neurogenesis. Furthermore, temporal translatome analyses of developing NSCs will provide valuable information to understand the role of translational control in NSC lineage progression. Addressing these and other questions related to translational mechanisms will ultimately help reveal a comprehensive picture of how gene expression instructs brain development and function under normal and disease conditions.
This work was supported by the Natural Sciences and Engineering Research Council (RGPIN-2018-04246). L.M. is supported by the Alberta Children’s Hospital Research Institute Graduate Scholarship. We thank Drs. Savraj Grewal, Tim Shutt, and Katherine Gratton for helpful discussions and reading the manuscript. We apologize to authors whose work could not be cited due to space limitation.
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