KIF21B is a kinesin protein that promotes intracellular transport and controls microtubule dynamics. We report three missense variants and one duplication in KIF21B in individuals with ...neurodevelopmental disorders associated with brain malformations, including corpus callosum agenesis (ACC) and microcephaly. We demonstrate, in vivo, that the expression of KIF21B missense variants specifically recapitulates patients' neurodevelopmental abnormalities, including microcephaly and reduced intra- and inter-hemispheric connectivity. We establish that missense KIF21B variants impede neuronal migration through attenuation of kinesin autoinhibition leading to aberrant KIF21B motility activity. We also show that the ACC-related KIF21B variant independently perturbs axonal growth and ipsilateral axon branching through two distinct mechanisms, both leading to deregulation of canonical kinesin motor activity. The duplication introduces a premature termination codon leading to nonsense-mediated mRNA decay. Although we demonstrate that Kif21b haploinsufficiency leads to an impaired neuronal positioning, the duplication variant might not be pathogenic. Altogether, our data indicate that impaired KIF21B autoregulation and function play a critical role in the pathogenicity of human neurodevelopmental disorder.
A tight regulation of neuron production is required to generate a functional cerebral cortex and is achieved by a proper balance between proliferation and differentiation of progenitor cells. Though ...the vitamin A (retinol) active derivative retinoic acid (RA) has been implicated as one of the signals acting during mammalian forebrain neurogenesis, its function at the onset of neurogenesis as well as during establishment of cortical layers and neuronal subtypes remains elusive. One limitation is that murine mutants for genes encoding key enzymes involved in RA synthesis die during early embryonic development. We analysed corticogenesis in Rdh10 null mutants, in which an RA deficiency is generated as the intracellular retinol to retinaldehyde conversion is abolished. When analysed at the latest stage before lethality occurs (embryonic day E13.5), the mutants show smaller telencephalic vesicles and the thickness of their cortical plate is strongly reduced. The first progenitors formed in the cortical plate are radial glial (RG) cells which generate neurons either directly, or through an indirect mechanism involving the production of intermediate neuronal progenitors (INPs) which then give rise to neurons. We show that in absence of RA, the RG progenitors proliferate less and prematurely produce neurons, leading to their depletion at E11.5. Furthermore, we could demonstrate that lack of RA impairs the generation of INPs at E13.5 and affects the cell cycle exit of progenitor cells during corticogenesis, altogether leading to a deficit in projection neurons and to microcephaly.
•Impairment of the retinoid signalling pathway during neurogenesis induces microcephaly.•The retinoic acid-deficient Rdh10 mutant displays less cortical projection neurons.•In Rdh10-knockout mice, premature neurogenesis leads to the depletion of progenitor cells.•Retinoic acid regulates the balance between direct and indirect neurogenesis.•Retinoic acid deficiency affects several genes, including Insm1 and CyclinD2.
De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we ...investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1
mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1
animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1
mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.
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.
Abstract
Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. ...Though KIF2A is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.
Le développement du cortex cérébral se déroule selon des étapes bien définies qui sont essentielles à la formation d’un cerveau fonctionnel. La perturbation de l’une ou plusieurs de ces étapes peut ...conduire à des malformations neuro-développementales, responsables de différents troubles cognitifs, d’épilepsies ou encore de déficience intellectuelle. De nombreuses mutations dans des gènes codant pour les tubulines ou bien les kinésines, sont retrouvées chez des individus présentant diverses anomalies neuro-développementales. Bien que les kinésines soient impliquées dans le développement cortical, les mécanismes fonctionnels par lesquels elles conduisent aux malformations demeurent encore méconnus. Mon travail de thèse identifie la kinésine Kif21b, jusqu’alors peu connue, comme étant essentielle au développement cortical. Nous montrons que Kif21b régule la migration neuronale dans le cortex et identifions quatre variants chez des individus présentant des malformations neuro-développementales. Nous montrons que l’expression ectopique des variants chez la souris et le poisson zèbre récapitulent les phénotypes observés chez ces patients.
The development of the cerebral cortex is a highly regulated process that is crucial for the establishment of functional cortical networks. Disruption of one or several of these steps can lead severe neurodevelopmental disorders that are associated with intellectual disabilities, epilepsies and cognitive impairment. Over the past few years, several genetic mutations in genes encoding either tubulin or microtubule-associated motors such as kinesins, have been found in individuals with neurodevelopmental disorders. Although kinesins have been found to be essential for a proper cortical development, the exact functions of kinesins in these processes are still poorly understood. My work clearly identified Kif21b, a poorly-known kinesin, as a novel key regulator of cortical development both in mouse and human. We show that Kif21b regulates both radial and tangential migration of cortical neurons, and identify four KIF21B variants in individuals presenting neurodevelopmental disorders. We show that ectopic expression of variants recapitulate phenotypes both in mice and zebrafish.
Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. Though KIF2A ...is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.
To evaluate the influence of long‐distance transport of charcoal particles on the detection of local wildfires from lake sediment sequences, we tracked three consecutive years of charcoal deposition ...into traps set within seven boreal lakes in northeastern Canada. Peaks in macroscopic charcoal accumulation (>150 µm) were linked to both local (inside the watershed) and regional wildfires. However, regional fires were characterized by higher proportions of small particles (<0.1 mm2) in charcoal assemblages. We conclude that the analysis of particle size distribution is useful to discriminate “true” local fires from regional wildfires.
Key Points
Charcoal accumulation was monitored during 3 years in seven lakesLocal (close) and regional (distant) wildfires both produced charcoal peaksLocal and regional fires had different charcoal size distributions
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