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• W2805557900 abstract "•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 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. 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. The cerebral cortex underwent a considerable increase in size and complexity over the last millions of years of hominid evolution, with significant impact on the acquisition of cognitive functions in the human species (Hill and Walsh, 2005Hill R.S. Walsh C.A. Molecular insights into human brain evolution.Nature. 2005; 437: 64-67Crossref PubMed Scopus (160) Google Scholar, Lui et al., 2011Lui J.H. Hansen D.V. 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Modeling human neural development with pluripotent stem cells.Development. 2015; 142: 3138-3150Crossref PubMed Scopus (75) Google Scholar). Species differences in cortical neurogenic output are also linked to the expansion of specific classes of progenitors in the primate and human cortex, in particular the “outer” radial glial (oRG) cells, located in the outer-subventricular zone (oSVZ) (Fietz et al., 2010Fietz S.A. Kelava I. Vogt J. Wilsch-Bräuninger M. Stenzel D. Fish J.L. Corbeil D. Riehn A. Distler W. Nitsch R. Huttner W.B. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling.Nat. Neurosci. 2010; 13: 690-699Crossref PubMed Scopus (571) Google Scholar, Hansen et al., 2010Hansen D.V. Lui J.H. Parker P.R. Kriegstein A.R. Neurogenic radial glia in the outer subventricular zone of human neocortex.Nature. 2010; 464: 554-561Crossref PubMed Scopus (895) Google Scholar, Reillo et al., 2011Reillo I. de Juan Romero C. 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Particularly interesting are hominid-specific duplicated (HS) genes, which arose from segmental DNA-mediated gene duplications specifically in the hominid and/or human genomes (Fortna et al., 2004Fortna A. Kim Y. MacLaren E. Marshall K. Hahn G. Meltesen L. Brenton M. Hink R. Burgers S. Hernandez-Boussard T. et al.Lineage-specific gene duplication and loss in human and great ape evolution.PLoS Biol. 2004; 2: E207Crossref PubMed Scopus (229) Google Scholar, Goidts et al., 2006Goidts V. Cooper D.N. Armengol L. Schempp W. Conroy J. Estivill X. Nowak N. Hameister H. Kehrer-Sawatzki H. Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome.Hum. Genet. 2006; 120: 270-284Crossref PubMed Scopus (55) Google Scholar, Marques-Bonet et al., 2009Marques-Bonet T. Kidd J.M. Ventura M. Graves T.A. Cheng Z. Hillier L.W. Jiang Z. Baker C. Malfavon-Borja R. 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Recent segmental duplications are enriched for gene families with potential roles in neural development (Fortna et al., 2004Fortna A. Kim Y. MacLaren E. Marshall K. Hahn G. Meltesen L. Brenton M. Hink R. Burgers S. Hernandez-Boussard T. et al.Lineage-specific gene duplication and loss in human and great ape evolution.PLoS Biol. 2004; 2: E207Crossref PubMed Scopus (229) Google Scholar, Sudmant et al., 2010Sudmant P.H. Kitzman J.O. Antonacci F. Alkan C. Malig M. Tsalenko A. Sampas N. Bruhn L. Shendure J. Eichler E.E. 1000 Genomes ProjectDiversity of human copy number variation and multicopy genes.Science. 2010; 330: 641-646Crossref PubMed Scopus (487) Google Scholar, Zhang et al., 2011Zhang Y.E. Landback P. Vibranovski M.D. Long M. 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Eichler E.E. 1000 Genomes ProjectDiversity of human copy number variation and multicopy genes.Science. 2010; 330: 641-646Crossref PubMed Scopus (487) Google Scholar), but very little information is available on their expression patterns. This is due to the difficulty to determine their expression level with conventional methods, given the high sequence similarity between HS paralogs of the same family. We first sought to determine, for each HS gene family, whether and how ancestral and paralog genes are expressed in the human developing cortex. We performed deep sequencing of RNA extracted from human fetal cortex at key stages of cortical neurogenesis (from 7 to 21 gestational weeks [GW]). For the later-stage samples, we performed microdissection to discriminate specific regions of the cortex (frontal to occipital). For the parietal area, we further microdissected the cortical plate (CP) and underlying domains of the cortical wall (non-CP, containing mostly oSVZ and VZ germinal zones) to isolate compartments enriched in neural progenitors versus postmitotic neurons. To maximize the sensitivity and specificity of HS gene detection, we selected the libraries for cDNA fragments of 350–700 bp and sequenced them with a 2 × 151 bp paired-ends protocol (Figure S1A). Since HS duplications are recent evolutionary events, paralogs within each family are highly similar, potentially confusing the mapping of reads originating from individual paralogs and estimates of their levels of expression (Figure S1B). Standard annotations on reference genomes are also discordant for HS genes. We therefore manually curated gene structures for these genes whenever possible (Table S1) and developed a computational pipeline correcting the expression estimates of closely related paralogs for mapping errors (Figures S1C and S1D; STAR Methods). We focused on gene duplications previously described in the human genome (Sudmant et al., 2010Sudmant P.H. Kitzman J.O. Antonacci F. Alkan C. Malig M. Tsalenko A. Sampas N. Bruhn L. Shendure J. Eichler E.E. 1000 Genomes ProjectDiversity of human copy number variation and multicopy genes.Science. 2010; 330: 641-646Crossref PubMed Scopus (487) Google Scholar) followed by homology searches at the genomic and transcript levels (Table S2). The distribution of gene expression values for HS genes was similar to that of all genes in the human reference genome (Figure 1A). We selected HS genes based on their absolute levels of expression above a defined threshold, 5 fragments per kilobase million (FPKM), corresponding to the minimal level of a set of 60 well-defined marker genes of corticogenesis (Figure 1A). We then selected the gene families where at least two paralogs, typically the ancestor and at least one HS paralog, were expressed above the threshold (Figure 1B). This selection led to a short list of 68 genes distributed among 24 gene families, displaying robust and dynamic expression during human corticogenesis (Figure 1B; Table S2). About half of the genes were preferentially expressed in progenitors and/or early stages, and fewer of them in neuronal compartment and/or late stages of corticogenesis (Figure 1C). Analysis of predicted coding sequences revealed that 51 HS genes (including 18 potential ancestor genes and 35 potentially unique to hominid and human genomes) display an open reading frame (ORF) that was overall conserved but distinct between paralogs of the same family. For 17 HS genes, no reliable ORF could be detected, indicating potential pseudogenization or function as non-coding RNA (Table S2). Among the HS genes that have been studied so far in the context of cortical development, the screen identified SRGAP2 family genes, but neither ARHGAP11 nor TBC1D3 as the expression of ARHGAP11B was below" @default.
• W2805557900 created "2018-06-13" @default.
• W2805557900 creator A5002062661 @default.
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• W2805557900 date "2018-05-01" @default.
• W2805557900 modified "2023-10-18" @default.
• W2805557900 title "Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation" @default.
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