The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), ...whose asymmetric division gives birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers ER stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development.
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•The UPR is a homeostat regulating the specification of cortical stem cells•Elp3 loss in cortical stem cells triggers UPR by decreasing codon translation rates•Gradual UPR suppression promotes the switch from direct to indirect neurogenesis
Laguesse, Creppe et al. demonstrate that the unfolded protein response (UPR) contributes to neurogenesis in the developing cerebral cortex. Depletion of the Elongator complex component Elp3 triggers the UPR through interference with codon translation speed. UPR activation impairs the balance between direct and indirect neurogenesis, leading to premature neuron generation.
The unfolded protein response (UPR) is a homeostatic signaling pathway triggered by protein misfolding in the endoplasmic reticulum (ER). Beyond its protective role, it plays important functions ...during normal development in response to elevated demand for protein folding. Several UPR effectors show dynamic temporal and spatial expression patterns that correlate with milestones of the central nervous system (CNS) development. Here, we discuss recent studies suggesting that a dynamic regulation of UPR supports generation, maturation, and maintenance of differentiated neurons in the CNS. We further highlight studies supporting a developmental vulnerability of CNS to UPR dysregulation, which underlies neurodevelopmental disorders. We believe that a better understanding of UPR functions may provide novel opportunities for therapeutic strategies to fight ER/UPR-associated human neurological disorders.
A defect in microtubule (MT)-based transport contributes to the neuronal toxicity observed in Huntington's disease (HD). Histone deacetylase (HDAC) inhibitors show neuroprotective effects in this ...devastating neurodegenerative disorder. We report here that HDAC inhibitors, including trichostatin A (TSA), increase vesicular transport of brain-derived neurotrophic factor (BDNF) by inhibiting HDAC6, thereby increasing acetylation at lysine 40 of alpha-tubulin. MT acetylation in vitro and in cells causes the recruitment of the molecular motors dynein and kinesin-1 to MTs. In neurons, acetylation at lysine 40 of alpha-tubulin increases the flux of vesicles and the subsequent release of BDNF. We show that tubulin acetylation is reduced in HD brains and that TSA compensates for the transport- and release-defect phenotypes that are observed in disease. Our findings reveal that HDAC6 inhibition and acetylation at lysine 40 of alpha-tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered.
Abstract
Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification ...is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.
Graphical Abstract
Graphical abstract
ADAT catalyses tRNAs wobble adenosine-to-inosine modification through ADAT3 recognition of tRNAs 3D structure and anticodon-loop presentation to ADAT2 catalytic subunit. ADAT3 V128M mutation hampers presentation, leading to neurodevelopmental disorders.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a family of multifunctional RNA-binding proteins able to process nuclear pre-mRNAs into mature mRNAs and regulate gene expression in ...multiple ways. They comprise at least 20 different members in mammals, named from A ( HNRNP A1 ) to U ( HNRNP U ). Many of these proteins are components of the spliceosome complex and can modulate alternative splicing in a tissue-specific manner. Notably, while genes encoding hnRNPs exhibit ubiquitous expression, increasing evidence associate these proteins to various neurodevelopmental and neurodegenerative disorders, such as intellectual disability, epilepsy, microcephaly, amyotrophic lateral sclerosis, or dementias, highlighting their crucial role in the central nervous system. This review explores the evolution of the hnRNPs family, highlighting the emergence of numerous new members within this family, and sheds light on their implications for brain development.
The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these ...neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.
The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major ...impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
Kinesin Family Member 21B (KIF21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin superfamily proteins, which play a key role in microtubule organisation in neuronal dendrites and axons. ...Recently, heterozygous variants in KIF21B were implicated as the cause of intellectual disability and brain malformations in four unrelated individuals. We report a 9-year-old male with delayed speech, hyperactivity, poor social interaction, and autistic features. A parent-offspring trio exome sequencing identified a novel de novo rare heterozygous variant, NM_001252102.2: c.1513A>C, p.(Ser505Arg) in exon 11 of KIF21B. In vivo functional analysis using in utero electroporation in mouse embryonic cortex revealed that the expression of Ser505Arg KIF21B protein in the cerebral cortex impaired the radial migration of projection neurons, thus confirming the pathogenicity of the variant. Our report further validates pathogenic variants in KIF21B as a cause of neurodevelopmental disorder.
The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work ...describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.
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•MicroRNAs control radial migration through regulation of cortical neuron polarization•miR-22 and miR-124 are critical regulators of neuron morphology during migration•miR-22 and miR-124 target the CoREST/REST complex to fine-tune doublecortin expression
The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive. In this study, Volvert et al. show that miR-22 and miR-124 are enriched in cortical neurons where they target CoREST to fine-tune expression of Dcx, thereby regulating their dynamic polarization and migration to the cortical plate.
Completion of neuronal migration is critical for brain development. Kif21b is a plus-end-directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in ...neurons. Here we report a physiological function of Kif21b during radial migration of projection neurons in the mouse developing cortex. In vivo analysis in mouse and live imaging on cultured slices demonstrate that Kif21b regulates the radial glia-guided locomotion of newborn neurons independently of its motility on microtubules. We show that Kif21b directly binds and regulates the actin cytoskeleton both in vitro and in vivo in migratory neurons. We establish that Kif21b-mediated regulation of actin cytoskeleton dynamics influences branching and nucleokinesis during neuronal locomotion. Altogether, our results reveal atypical roles of Kif21b on the actin cytoskeleton during migration of cortical projection neurons.
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•Kif21b regulates neuronal migration independently of its motility on microtubules•Kif21b regulates actin cytoskeleton dynamics through direct binding•Kif21b function during nucleokinesis relies on the regulation of the actomyosin network•Kif21b fine-tunes actin dynamics during pausing and branching of migrating neurons
Rivera Alvarez et al. show that the kinesin Kif21b regulates the migration of cortical neurons independently of its well-characterized motility function on microtubules. The authors demonstrate that Kif21b is an actin-binding protein that modulates both actin dynamics and actomyosin contraction in migrating neurons.
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