A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
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ABSTRACT:
PROVIDER: PRJNA873102 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21195526_1.fastq.gz | Fastqsanger.gz | |||
| SRR21195526_2.fastq.gz | Fastqsanger.gz | |||
| SRR21195527_1.fastq.gz | Fastqsanger.gz | |||
| SRR21195527_2.fastq.gz | Fastqsanger.gz | |||
| SRR21195528_1.fastq.gz | Fastqsanger.gz |
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Project description:The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, mainly results from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lisencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion; that oRGs are necessary for neocortical folding; and that defects in oRG expansion may cause primary microcephaly.
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Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals. We performed gene expression microarray analysis on embryonic mouse cerebral cortex derived from Trnp1 knockdown and control animals.
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Project description:Cell type composition and circuit organization of neocortical radial clones
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Project description:Excitatory neurons arising from a common progenitor establish radially-oriented clonal units in the neocortex which have been proposed to serve as elementary information processing modules. To characterize the cell types and circuit diagram within these clonal units, we performed single-cell RNA-sequencing and multi-cell patch clamp recordings of neurons derived from Nestin-positive progenitors. We found that radial clones do not appear to be fate-restricted, but instead individual clones are composed of a random sampling of the transcriptomic cell types present in a particular cortical area. The effect of lineage on synaptic connectivity depends on the type of connection tested: pairs of clonally related neurons were more likely to be connected vertically, across cortical layers, but not laterally within the same layer, compared to unrelated pairs. We propose that integration of vertical input from related neurons with lateral input from unrelated neurons may represent a developmentally programmed motif for assembling neocortical circuits.
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Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals.
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Project description:A massively expanded outer subventricular zone (OSVZ) in the primate and human has been proposed for generating majority of neocortical neurons, which consists of basally located radial glia cells. Previous studies with various strategies have tried to recognize genes specifically expressed in those cells; however, the molecular and cellular features of these cells still remain uncertain. By profiling gene expression across single cells isolated from cellular anatomy location and subtype sorting, we identified a primate-specific gene TMEM14B as a novel marker for basally located radial glia. Expression of TMEM14B induced dramatic increase in the number of radial glial and OSVZ region. Finally, we found that OSVZ progenitor’s extensive proliferative potential was up regulated through IQGAP1 phosphorylation and nuclear translocation, and remarkably, led to the gyrification in postnatal mouse. These results highlight that evolutionary expansion promoted by primate-specific genes enabling the evolutionary expansion and folding of the human neocortex.
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Project description:Precise spatiotemporal control of mRNA translation machinery is essential to proper development of highly complex systems like the neocortex. Here, we show that an RNA-binding protein, Hu antigen R (HuR), regulates both neocorticogenesis and specificity of neocortical translation machinery in a developmental stagedependent manner in mice. Neocortical absence of HuR alters the phosphorylation states of the initiation and elongation factors of the core translation machinery. In addition, HuR regulates the temporally specific positioning of functionally related mRNAs into the active translation sites, the polysomes. HuR also determines the specificity of neocortical polysomes by defining their combinatorial composition of ribosomal proteins and initiation and elongation factors. For some of the HuR-dependent proteins, the association with polysomes depends on the eIF2 alpha kinase 4 (eIF2ak4), which associated with HuR in prenatal developing neocortices. Finally, we found that deletion of HuR prior to embryonic day 10 (E10) disrupts both neocortical lamination and formation of the main neocortical commissure, the corpus callosum. Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity. Cortex was dissected from mouse pups at embryonic day 13 (E13) or the day of birth (P0).
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Project description:Analysis of gene expression over serial 150um sections of a single gestational week 14.5 human neocortical specimen. The hypothesis tested with this dataset was that a transcriptional signature of radial glia (neural stem cells) could be isolated via unsupervised gene coexpression analysis due to variation in the abundance of this cell type from section to section. This dataset is the first of its kind generated using this method (Gene Coexpression Analysis of Serial Sections, or GCASS).
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