Humans had acquired a tremendously enlarged cerebral cortex containing a huge quantity and variety of cells during evolution. Such evolutionary uniqueness offers a neural basis of our cognitive ...innovation and human‐specific features of neurodevelopmental and psychiatric disorders. Since human brain is hardly examined in vivo with experimental approaches commonly applied on animal models, the recent advancement of sequencing technologies offers an indispensable viewpoint of human brain anatomy and development. This review introduces the recent findings on the unique features in the adult and the characteristic developmental processes of the human cerebral cortex, based on high‐throughput DNA sequencing technologies.
The cerebral cortex underwent rapid expansion and increased complexity during recent hominid evolution. Gene duplications constitute a major evolutionary force, but their impact on human brain ...development remains unclear. Using tailored RNA sequencing (RNA-seq), we profiled the spatial and temporal expression of hominid-specific duplicated (HS) genes in the human fetal cortex and identified a repertoire of 35 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among them NOTCH2NL, human-specific paralogs of the NOTCH2 receptor, stood out for their ability to promote cortical progenitor maintenance. NOTCH2NL promote the clonal expansion of human cortical progenitors, ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL function by activating the Notch pathway through inhibition of cis Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes active during human corticogenesis and reveals how human-specific NOTCH paralogs may have contributed to the expansion of the human cortex.
Display omitted
•Identification of >35 HS protein-coding genes expressed during human corticogenesis•NOTCH2NL human-specific paralogs of NOTCH2 expressed in human cortical progenitors•NOTCH2NL genes expand human cortical progenitors and their neuronal output•NOTCH2NL promotes Notch signaling through cis-inhibition of Delta/Notch interactions
Human-specific NOTCH2NL expands cortical progenitors and neuronal output and thus may have contributed to the expansion of the human cortex.
The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the ...poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution.
The six-layered neocortex permits complex information processing in all mammalian species. Because its homologous region (the pallium) in nonmammalian amniotes has a different architecture, the ...ability of neocortical progenitors to generate an orderly sequence of distinct cell types was thought to have arisen in the mammalian lineage. This study, however, shows that layer-specific neuron subtypes do exist in the chick pallium. Deep- and upper-layer neurons are not layered but are segregated in distinct mediolateral domains in vivo. Surprisingly, cultured chick neural progenitors produce multiple layer-specific neuronal subtypes in the same chronological sequence as seen in mammals. These results suggest that the temporal sequence of the neocortical neurogenetic program was already inherent in the last common ancestor of mammals and birds and that mammals use this conserved program to generate a uniformly layered neocortex, whereas birds impose spatial constraints on the sequence to pattern the pallium.
Display omitted
Display omitted
► Layer-specific neuron subtypes of the mammalian neocortex exist in the chick pallium ► Deep- and upper-layer neurons are generated by distinct progenitors in chick in vivo ► The layer-specific neurons are sequentially generated by common progenitors in vitro ► Neocortical neurogenetic program existed before the emergence of layer structure
Suzuki et al. find that “layer-specific” neuron subtypes typical of mammalian neocortex are arranged mediolaterally in the chick pallium. Their results indicate that mammalian neocortical and chick pallial progenitors use the same temporally ordered neurogenetic program to generate subtype-specific progeny, but chick pallial output is spatially constrained by developmental patterning.
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide ...range of clinical manifestations in NIID makes ante-mortem diagnosis difficult
, but skin biopsy enables its ante-mortem diagnosis
. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.
Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV-associated microcephaly remains unclear. ...We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice.
This study describes a co-culture system of human skin equivalents (HSEs) and dorsal root ganglion (DRG) neurons. We prepared spheroids of mouse DRG neurons with or without Schwann cells (SCs). ...Spheroids comprising DRG neurons and SCs showed longer neurite extensions than those comprising DRG neurons alone. Neurite extension of more than 1 mm was observed from spheroids cultured inside HSEs, whereas neurite extension was primarily observed on the surface of HSEs from spheroids cultured on HSEs. We propose that our model may be a useful tool for studying neurite extension in the human skin.
Display omitted
•In silico analysis of DCLK1 transcripts reveals developmental dynamics unique for each isoform.•DCLK1 isoforms are distributed in the partially distinct brain regions.•Overexpression of DCLK1-L in ...progenitors causes neural migration defects.•The migration defects by DCLK1-L overexpression requires its kinase activity
Doublecortin-like kinase 1 (DCLK1) is a Doublecortin family kinase involved in a range of brain development processes including cell migration, axon/dendrite growth, and synapse development. The Dclk1 gene potentially generates multiple splicing isoforms, but the detailed expression patterns in the brain as well as in vivo functions of each isoform are still incompletely understood. Here we assessed expression patterns of DCLK1 isoforms using multiple platforms including in silico, in situ, and in vitro datasets in the developing mouse brain, and show quantitative evidence that among the four DCLK1 isoforms, DCLK1-L and DCL are mainly expressed in the embryonic cortex whereas DCLK1-L and CPG16 become dominant compared to DCL and CARP in the postnatal cortex. We also provide compelling evidence that DCLK1 isoforms are distributed in the partially distinct brain regions in the embryonic and the postnatal stages. We further show that overexpression of DCLK1-L, but not the other isoforms, in neural progenitors causes severe migration defects in the cortex, and that the migration defects are dependent on the kinase activity of DCLK1-L. Our data thus uncover partially segregated localization of DCLK1 isoforms in the developing mouse brain and suggest different roles for distinct DCLK1 isoforms in the brain development and function.
The primary cilium is a central signaling component during embryonic development. Here we focus on CROCCP2, a hominid-specific gene duplicate from ciliary rootlet coiled coil (CROCC), also known as ...rootletin, that encodes the major component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex and human cortical cells and organoids results in decreased ciliogenesis and increased cortical progenitor amplification, particularly basal progenitors. CROCCP2 decreases ciliary dynamics by inhibition of the IFT20 ciliary trafficking protein, which then impacts neurogenesis through increased mTOR signaling. Loss of function of CROCCP2 in human cortical cells and organoids leads to increased ciliogenesis, decreased mTOR signaling, and impaired basal progenitor amplification. These data identify CROCCP2 as a human-specific modifier of cortical neurogenesis that acts through modulation of ciliary dynamics and mTOR signaling.
Display omitted
•CROCCP2: a hominid-specific gene duplicate uniquely expressed in human fetal cortex•CROCCP2 overexpression in the mouse embryo leads to cortical progenitor amplification•CROCCP2 is required for basal progenitor amplification in human cortical organoids•CROCCP2 acts by decreasing ciliogenesis and enhancing the mTOR pathway
van Heurck et al. identify CROCCP2, a hominid-specific gene duplicate, as a human-specific modifier of neurogenesis in the developing cerebral cortex. They find that CROCCP2 is necessary and sufficient to enhance human cortical progenitor amplification and acts by decreasing primary cilia dynamics and enhancing the mTOR pathway.
mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in polarized, elongated cells. These features are especially prominent in radial ...glial cells (RGCs), which are neural and glial precursors of the developing cerebral cortex and scaffolds for migrating neurons. Yet the mechanisms by which subcellular RGC compartments accomplish their diverse functions are poorly understood. Here, we demonstrate that mRNA localization and local translation of the RhoGAP ARHGAP11A in the basal endfeet of RGCs control their morphology and mediate neuronal positioning. Arhgap11a transcript and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by the 5′ UTR. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to the basal endfeet, where ARHGAP11A is locally synthesized. This translation is essential for positioning interneurons at the basement membrane. Thus, local translation spatially and acutely activates Rho signaling in RGCs to compartmentalize neural progenitor functions.
Display omitted
•Arhgap11a subcellularly localizes in radial glia of mouse and human cerebral cortex•Arhgap11a 5′ UTR directs active transport and local translation in radial glia•Localized mRNA and RhoA-GAP activity controls radial glial endfoot morphology•Arhgap11a non-cell autonomously acts in radial glia to mediate interneuron position
Pilaz et al. demonstrate that Arhgap11a mRNA undergoes active transport and local translation in radial glial basal endfeet, which is essential for proper endfeet morphology. Further, Arhgap11a non-cell autonomously impacts positioning of interneurons and excitatory neurons. This demonstrates the functions of local translation in radial glial progenitors.
PDF
