Cortical Neurogenesis Research Articles

Impaired Cell Cycle Progression and Self-Renewal of Fetal Neural Stem and Progenitor Cells in a Murine Model of Intrauterine Growth Restriction

Individuals with intrauterine growth restriction (IUGR) are at an increased risk for neurodevelopmental impairment. Fetal cortical neurogenesis is a time-sensitive process in which fetal neural stem cells (NSCs) follow a distinct pattern of layer-specific neuron generation to populate the cerebral cortex. Here, we used a murine maternal hypoxia-induced IUGR model to study the impact of IUGR on fetal NSC development. In this model, timed-pregnant mice were exposed to hypoxia during the active stage of neurogenesis, followed by fetal brain collection and analysis. In the IUGR fetal brains, we found a significant reduction in cerebral cortical thickness accompanied by decreases in layer-specific neurons. Using EdU labeling, we demonstrated that cell cycle progression of fetal NSCs was delayed, primarily observed in the G2/M phase during inward interkinetic nuclear migration. Following relief from maternal hypoxia exposure, the remaining fetal NSCs re-established their neurogenic ability and resumed production of layer-specific neurons. Surprisingly, the newly generated neurons matched their control counterparts in layer-specific marker expression, suggesting preservation of the fetal NSC temporal identity despite IUGR effects. As expected, the absolute number of neurons generated in the IUGR group remained lower compared to that in the control group due to a reduced fetal NSC pool size as a result of cell cycle defect. Transcriptome analysis identified genes related to energy expenditure and G2/M cell cycle progression being affected by maternal hypoxia-induced IUGR. Taken together, maternal hypoxia-induced IUGR is associated with a defect in cell cycle progression of fetal NSCs, and has a long-term impact on offspring cognitive development.

Evolution of genetic mechanisms regulating cortical neurogenesis.

The size of the cerebral cortex increases dramatically across amniotes, from reptiles to great apes. This is primarily due to different numbers of neurons and glial cells produced during embryonic development. The evolutionary expansion of cortical neurogenesis was linked to changes in neural stem and progenitor cells, which acquired increased capacity of self‐amplification and neuron production. Evolution works via changes in the genome, and recent studies have identified a small number of new genes that emerged in the recent human and primate lineages, promoting cortical progenitor proliferation and increased neurogenesis. However, most of the mammalian genome corresponds to noncoding DNA that contains gene‐regulatory elements, and recent evidence precisely points at changes in expression levels of conserved genes as key in the evolution of cortical neurogenesis. Here, we provide an overview of basic cellular mechanisms involved in cortical neurogenesis across amniotes, and discuss recent progress on genetic mechanisms that may have changed during evolution, including gene expression regulation, leading to the expansion of the cerebral cortex.

Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome.

Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as β-amyloid (APP/Aβ and Aβ1–42) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aβ immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS.

Regulation of Cell Delamination During Cortical Neurodevelopment and Implication for Brain Disorders.

Cortical development is dependent on key processes that can influence apical progenitor cell division and progeny. Pivotal among such critical cellular processes is the intricate mechanism of cell delamination. This indispensable cell detachment process mainly entails the loss of apical anchorage, and subsequent migration of the mitotic derivatives of the highly polarized apical cortical progenitors. Such apical progenitor derivatives are responsible for the majority of cortical neurogenesis. Many factors, including transcriptional and epigenetic/chromatin regulators, are known to tightly control cell attachment and delamination tendency in the cortical neurepithelium. Activity of these molecular regulators principally coordinate morphogenetic cues to engender remodeling or disassembly of tethering cellular components and external cell adhesion molecules leading to exit of differentiating cells in the ventricular zone. Improper cell delamination is known to frequently impair progenitor cell fate commitment and neuronal migration, which can cause aberrant cortical cell number and organization known to be detrimental to the structure and function of the cerebral cortex. Indeed, some neurodevelopmental abnormalities, including Heterotopia, Schizophrenia, Hydrocephalus, Microcephaly, and Chudley-McCullough syndrome have been associated with cell attachment dysregulation in the developing mammalian cortex. This review sheds light on the concept of cell delamination, mechanistic (transcriptional and epigenetic regulation) nuances involved, and its importance for corticogenesis. Various neurodevelopmental disorders with defective (too much or too little) cell delamination as a notable etiological underpinning are also discussed.

ALFY localizes to early endosomes and cellular protrusions to facilitate directional cell migration.

ABSTRACTCell migration is a complex process underlying physiological and pathological processes such as brain development and cancer metastasis. The autophagy-linked FYVE protein (ALFY; also known as WDFY3), an autophagy adaptor protein known to promote clearance of protein aggregates, has been implicated in brain development and neural migration during cerebral cortical neurogenesis in mice. However, a specific role of ALFY in cell motility and extracellular matrix adhesion during migration has not been investigated. Here, we reveal a novel role for ALFY in the endocytic pathway and in cell migration. We show that ALFY localizes to RAB5- and EEA1-positive early endosomes in a PtdIns(3)P-dependent manner and is highly enriched in cellular protrusions at the leading and lagging edge of migrating cells. We find that cells lacking ALFY have reduced attachment and altered protein levels and glycosylation of integrins, resulting in the inability to form a proper leading edge and loss of directional cell motility.

Early postnatal handling alters social behavior, learning, and memory of pre- and postnatal VPA-induced rat models of autism in a context-based manner

Early life events are known to greatly affect brain development, cortical neurogenesis, and Hypothalamic-pituitary-adrenal activity. Mainly characterized by impairment in social communication, language, and cognitive development, autism spectrum disorder (ASD) refers to a class of neuropsychiatric disorders with numerous genetic and environmental risk factors. In the early handling (EH) method, daily separation of infants from their mother, physical touching, and exposure to a new environment occur. Here, we studied the effect of EH on Social interaction, learning, and memory in rats exposed pre-or post-natally to valproic acid (VPA). Gestational VPA exposure (600 mg/kg) led to some severe autistic-like traits, more notable in the social behavior of the male sex, along with unchanged to partially altered spatial learning and memory function and reduced avoidance memory. In comparison, while causing a sex-dependent increase in spatial memory, subcutaneous injection of VPA (400 mg/kg) in infancy resulted in limited adverse autistic features, including a decrease in males’ social preference, as well as reduced avoidance memory. The results indicated that neonatal handling significantly improved multiple social behavior and memory deficits in prenatally injected rats. In contrast, EH in rats receiving postnatal VPA elicited a restricted advantage on social novelty tendency; while negatively affecting some other social behavior criteria and spatial learning of males and encouraging sex-dependent repetitive behaviors in the social setting. The controversial influence of postnatal handling on juvenile rats of postnatal VPA treatment vs. prenatal VPA treatment opens up the potential for future research on the context-based consequence of early-life handling stress using different behavioral tasks and to benefit therapeutic procedures through understanding the sex- and age-specific neurobiology of short-term environmental manipulation in animal models of autism.

Long-Term Functional and Cytoarchitectonic Effects of the Systemic Administration of the Histamine H1 Receptor Antagonist/Inverse Agonist Chlorpheniramine During Gestation in the Rat Offspring Primary Motor Cortex.

The transient histaminergic system is among the first neurotransmitter systems to appear during brain development in the rat mesencephalon/rhombencephalon. Histamine increases FOXP2-positive deep-layer neuron differentiation of cortical neural stem cells through H1 receptor activation in vitro. The in utero or systemic administration of chlorpheniramine (H1 receptor antagonist/inverse agonist) during deep-layer cortical neurogenesis decreases FOXP2 neurons in the developing cortex, and H1R- or histidine decarboxylase-knockout mice show impairment in learning and memory, wakefulness and nociception, functions modulated by the cerebral cortex. Due to the role of H1R in cortical neural stem cell neurogenesis, the purpose of this study was to evaluate the postnatal impact of the systemic administration of chlorpheniramine during deep-layer cortical neuron differentiation (E12–14) in the primary motor cortex (M1) of neonates (P0) and 21-day-old pups (P21). Chlorpheniramine or vehicle were systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats at gestational days 12–14, and the expression and distribution of deep- (FOXP2 and TBR1) and superficial-layer (SATB2) neuronal cortical markers were analyzed in neonates from both groups. The qRT-PCR analysis revealed a reduction in the expression of Satb2 and FoxP2. However, Western blot and immunofluorescence showed increased protein levels in the chlorpheniramine-treated group. In P21 pups, the three markers showed impaired distribution and increased immunofluorescence in the experimental group. The Sholl analysis evidenced altered dendritic arborization of deep-layer neurons, with lower excitability in response to histamine, as evaluated by whole-cell patch-clamp recording, as well as diminished depolarization-evoked [3H]-glutamate release from striatal slices. Overall, these results suggest long-lasting effects of blocking H1Rs during early neurogenesis that may impact the pathways involved in voluntary motor activity and cognition.

Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction. Our data from human embryonic stem cells, when combined with analysis of available foetal cortical gene expression data, de novo rare variants and GWAS statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.

Monosialotetrahexosylganglioside Sodium Promotes the Cortical Neurogenesis in Traumatic Brain Injury Rats

To explore the effect of monosialotetrahexosylganglioside sodium on cortical neurogenesis in traumatic brain injury rats. Thirty Sprague–Dawley rats were randomly divided into the control group, the saline group and the monosialotetrahexosylganglioside sodium group. The rats traumatic brain injury model of saline group and the monosialotetrahexosylganglioside sodium group, control group rats was prepared with hydraulic controllable injury device and control group received sham operation. The levels of oxidative stress, nerve damage, cortical new born neurons, learning and memory capabilities of rats were assessed with serum malondialdehyde and superoxide dismutase levels, serum neurofilament light level and terminal deoxynucleotidyl transferase dUTP nick end labeling, neuronal nuclear protein/ bromodeoxyuridine cells and Morris water maze respectively. Compared with the control group, the level of oxidative stress was significantly increased, the nerve damage was obvious, the number of new born neurons increased, and the ability of learning and memory decreased in the other two groups. Compared with the normal saline group, the oxidative stress level was lower, the nerve damage was reduced, the number of new born neurons increases more obviously and the decline in learning and memory ability was reduced in the monosialotetrahexosylganglioside sodium group. Monosialotetrahexosylganglioside sodium can reduce the oxidative stress level, protect the nerve cells from damage and promote the neurogenesis in the cortex and promote the improvement of cognitive functions such as learning and memory in traumatic brain injury rats.

Psychiatric risk gene transcription factor 4 preferentially regulates cortical interneuron neurogenesis during early brain development.

Genetic variants within or near the transcription factor 4 gene (TCF4) are robustly implicated in psychiatric disorders including schizophrenia. However, the biological pleiotropy poses considerable obstacles to dissect the potential relationship between TCF4 and those highly heterogeneous diseases. Through integrative transcriptomic analysis, we demonstrated that TCF4 is preferentially expressed in cortical interneurons during early brain development. Therefore, disruptions of interneuron development might be the underlying contribution of TCF4 perturbation to a range of neurodevelopmental disorders. Here, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 on human medial ganglionic eminence-like organoids (hMGEOs) to identify genome-wide TCF4 binding sites, followed by integration of multi-omics data from human fetal brain. We observed preferential expression of the isoform TCF4-B over TCF4-A. De novo motif analysis found that the identified 5916 TCF4 binding sites are significantly enriched for the E-box sequence. The predicted TCF4 targets in general have positively correlated expression levels with TCF4 in the cortical interneurons, and are primarily involved in biological processes related to neurogenesis. Interestingly, we found that TCF4 interacts with non-bHLH proteins such as FOS/JUN, which may underlie the functional specificity of TCF4 in hMGEOs. This study highlights the regulatory role of TCF4 in interneuron development and provides compelling evidence to support the biological rationale linking TCF4 to the developing cortical interneuron and psychiatric disorders.

Sensitive Periods for Recovery from Early Brain Injury.

The developing brain is remarkably plastic as it changes in response to a wide range of experiences including sensory and motor experience, psychoactive drugs, peer relationships, parent-infant interactions, gonadal hormones, intestinal flora, diet, and injury. There are sensitive periods for many of these experiences, including cerebral injury. Comparisons across mammalian species (humans, monkeys, cats, rats, mice) show a sensitive period for good outcomes from cerebral injury around the time of intense synaptogenesis. This period is postnatal in humans, cats, and rats, but prenatal in monkeys, reflecting the differences in neuronal development at birth across species. In addition, there appears to be a sensitive period prenatally during the time of maximum cortical neurogenesis and possibly during adolescence as well, although these periods are not as well studied as the period related to synaptogenesis and to date only examined in rats. Here we review the evidence for sensitive periods related to brain injury across species and propose mechanisms that may underlie the plasticity during these periods.

PDK1 Regulates the Lengthening of G1 Phase to Balance RGC Proliferation and Differentiation during Cortical Neurogenesis.

During cortical development, the balance between progenitor self-renewal and neurogenesis is critical for determining the size/morphology of the cortex. A fundamental feature of the developing cortex is an increase in the length of G1 phase in RGCs over the course of neurogenesis, which is a key determinant of progenitor fate choice. How the G1 length is temporally regulated remains unclear. Here, Pdk1, a member of the AGC kinase family, was conditionally disrupted by crossing an Emx1-Cre mouse line with a Pdk1fl/fl line. The loss of Pdk1 led to a shorter cell cycle accompanied by increased RGC proliferation specifically at late rather than early/middle neurogenic stages, which was attributed to impaired lengthening of G1 phase. Coincidently, apical-to-basal interkinetic nuclear migration was accelerated in Pdk1 cKO cortices. Consequently, we detected an increased neuronal output at P0. We further showed the significant upregulation of the cell cycle regulator cyclin D1 and its activator Myc in the cKO cortices relative to those of control animals. Overall, we have identified a novel role for PDK1 in cortical neurogenesis. PDK1 functions as an upstream regulator of the Myc-cyclin D1 pathway to control the lengthening of G1 phase and the balance between RGC proliferation and differentiation.

The Effect of Intravenously and Intra-arterially Delivered Human Umbilical Cord Blood Mononuclear Cell on Cortical Neurogenesis of Post-Ischemic Stroke Rat Brain

BACKGROUND: Stroke is the second most cause of death in the world. There are several treatments but they often end up with disabilities. Recently, cell therapy has become a new hope as an alternative treatment as it could improve the patients neurological deficits and daily living activities. Cord blood mononuclear cells (CB-MNCs) are one of the cell therapies for post-ischemic neurogenesis by intravenous or intra-arterial administration; however, it is not clear which one is better. AIM: This study aims to compare the effects of intra-arterial and intravenous administration of human CB-MNC on cortical neurogenesis of rat brain after ischemic stroke. METHODS: Twenty-four rats were divided into four groups, that is, control, middle cerebral artery obstruction (MCAO) without treatment, MCAO with intra-arterial CB-MNC injection (MCAO-IA), and MCAO with intravenous CB-MNC injection (MCAO-IV). Two weeks after injection, all rats were sacrificed, the brain was harvested, histologically process and stained with hematoxylin eosin (HE) to determine cellular and tissue morphology changes, and immunohistochemical staining, anti-NeuN antibody to determine the number of cortical neurons. The HE showed that MCAO rat brain had gliosis and shrunken cells. RESULTS: The results showed that MCAO-IA and MCAO-IV had fewer areas of gliosis and shrunken cells when compared to the MCAO group. The number of neurons also showed an increase. However, there was no difference between the MCAO-IA and MCAO-IV groups. It was concluded both of them could improve neurogenesis. CONCLUSION: CB-MNC administration can be an alternative for stroke ischemic therapy because it is proven to increase neurogenesis and reduce gliosis areas. However, there was no difference in neurogenesis in the brain tissue of mice injected with CB-MNC intravenously or intra-arterially.

The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review.

The human-specific gene NOTCH2NLC is primarily expressed in radial glial cells and plays an important role in neuronal differentiation and cortical neurogenesis. Increasing studies were conducted to verify the relationship between NOTCH2NLC gene and many neurological diseases, such as neuronal intranuclear inclusion disease, essential tremor, multiple system atrophy, Parkinson's disease, Alzheimer's disease, and even oculopharyngodistal myopathy. Thus, we support the concept, NOTCH2NLC-related GGC repeat expansion disorders (NRED), to summarize all diseases with the GGC repeat expansion in the 5'UTR of NOTCH2NLC gene, regardless of their various clinical phenotypes. Here, we discuss the reported cases to analyze the clinical features of NOTCH2NLC-related GGC repeat expansion disorders, including dementia, parkinsonism, peripheral neuropathy and myopathy, leukoencephalopathy, and essential tremor. In addition, we outline radiological and pathological manifestations of NOTCH2NLC-related GGC repeat expansion disorders, and then present possible mechanisms, such as toxic polyG protein, toxic repeat RNA, the GGC repeat size, and the size and types of trinucleotide interruption. Therefore, this review provides a systematic description of NOTCH2NLC-related GGC repeat expansion disorders and emphasizes the significance for understanding this type of repeat expansion disease.

Genes Associated with Disturbed Cerebral Neurogenesis in the Embryonic Brain of Mouse Models of Down Syndrome.

Down syndrome (DS), also known as trisomy 21, is the most frequent genetic cause of intellectual disability. Although the mechanism remains unknown, delayed brain development is assumed to be involved in DS intellectual disability. Analyses with human with DS and mouse models have shown that defects in embryonic cortical neurogenesis may lead to delayed brain development. Cre-loxP-mediated chromosomal engineering has allowed the generation of a variety of mouse models carrying various partial Mmu16 segments. These mouse models are useful for determining genotype–phenotype correlations and identifying dosage-sensitive genes involved in the impaired neurogenesis. In this review, we summarize several candidate genes and pathways that have been linked to defective cortical neurogenesis in DS.

Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development.

ObjectiveNeurodevelopmental diseases are common disorders caused by the disruption of essential neurodevelopmental processes. Recent human exome sequencing and genome‐wide association studies have shown that mutations in the subunits of the SWI/SNF (BAF) complex are risk factors for neurodevelopmental diseases. Clinical studies have found that ARID1A (BAF250a) is the most frequently mutated SWI/SNF gene and its mutations lead to mental retardation and microcephaly. However, the function of ARID1A in brain development and its underlying mechanisms still remain elusive.MethodsThe present study used Cre/loxP system to generate an Arid1a conditional knockout mouse line. Cell proliferation, cell apoptosis and cell differentiation of NSPCs were studied by immunofluorescence staining. In addition, RNA‐seq and RT‐PCR were performed to dissect the molecular mechanisms of Arid1a underlying cortical neurogenesis. Finally, rescue experiments were conducted to evaluate the effects of Neurod1 or Fezf2 overexpression on the differentiation of NSPCs in vitro.ResultsConditional knockout of Arid1a reduces cortical thickness in the developing cortex. Arid1a loss of function inhibits the proliferation of radial glial cells, and increases cell death during late cortical development, and leads to dysregulated expression of genes associated with proliferation and differentiation. Overexpression of Neurod1 or Fezf2 in Arid1a cKO NSPCs rescues their neural differentiation defect in vitro.ConclusionsThis study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of NSPCs during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations.

Greater Number of Microglia in Telencephalic Proliferative Zones of Human and Nonhuman Primate Compared with Other Vertebrate Species.

Microglial cells, the innate immune cells of the brain, are derived from yolk sac precursor cells, begin to colonize the telencephalon at the onset of cortical neurogenesis, and occupy specific layers including the telencephalic proliferative zones. Microglia are an intrinsic component of cortical germinal zones, establish extensive contacts with neural precursor cells (NPCs) and developing cortical vessels, and regulate the size of the NPC pool through mechanisms that include phagocytosis. Microglia exhibit notable differences in number and distribution in the prenatal neocortex between rat and old world nonhuman primate telencephalon, suggesting that microglia possess distinct properties across vertebrate species. To begin addressing this subject, we quantified the number of microglia and NPCs in proliferative zones of the fetal human, rhesus monkey, ferret, and rat, and the prehatch chick and turtle telencephalon. We show that the ratio of NPCs to microglia varies significantly across species. Few microglia populate the prehatch chick telencephalon, but the number of microglia approaches that of NPCs in fetal human and nonhuman primate telencephalon. These data demonstrate that microglia are in a position to perform important functions in a number of vertebrate species but more heavily colonize proliferative zones of fetal human and rhesus monkey telencephalon.

NOCICEPTRA: Gene and microRNA Signatures and Their Trajectories Characterizing Human iPSC-Derived Nociceptor Maturation.

Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders. Since native human nociceptors are hardly available for mechanistic functional research, and rodent models do not necessarily mirror human pathologies in all aspects, human induced pluripotent stem cell‐derived nociceptors (iDN) offer superior advantages as a human model system. Unbiased mRNA::microRNA co‐sequencing, immunofluorescence staining, and qPCR validations, reveal expression trajectories as well as miRNA target spaces throughout the transition of pluripotent cells into iDNs. mRNA and miRNA candidates emerge as regulatory hubs for neurite outgrowth, synapse development, and ion channel expression. The exploratory data analysis tool NOCICEPTRA is provided as a containerized platform to retrieve experimentally determined expression trajectories, and to query custom gene sets for pathway and disease enrichments. Querying NOCICEPTRA for marker genes of cortical neurogenesis reveals distinct similarities and differences for cortical and peripheral neurons. The platform provides a public domain neuroresource to exploit the entire data sets and explore miRNA and mRNA as hubs regulating human nociceptor differentiation and function.

Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

The role of WNT/β‐catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/β‐catenin regulates progenitor self‐renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)‐mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y‐like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1‐deficient apical progenitors show reduced asymmetric division due to an increase in apical–basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.

How neural stem cells contribute to neocortex development.

The mammalian neocortex is the seat of higher cognitive functions, such as thinking and language in human. A hallmark of the neocortex are the cortical neurons, which are generated from divisions of neural progenitor cells (NPCs) during development, and which constitute a key feature of the well-organized layered structure of the neocortex. Proper formation of neocortex structure requires an orchestrated cellular behavior of different cortical NPCs during development, especially during the process of cortical neurogenesis. Here, we review the great diversity of NPCs and their contribution to the development of the neocortex. First, we review the categorization of NPCs into different classes and types based on their cell biological features, and discuss recent advances in characterizing marker expression and cell polarity features in the different types of NPCs. Second, we review the different modes of cell divisions that NPCs undergo and discuss the importance of the balance between proliferation and differentiation of NPCs in neocortical development. Third, we review the different proliferative capacities among different NPC types and among the same type of NPC in different mammalian species. Dissecting the differences between NPC types and differences among mammalian species is beneficial to further understand the development and the evolutionary expansion of the neocortex and may open up new therapeutic avenues for neurodevelopmental and psychiatric disorders.