Hominin-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA435875 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6781100.fastq.gz | Fastqsanger.gz | |||
| SRR6781110.fastq.gz | Fastqsanger.gz | |||
| SRR6781101.fastq.gz | Fastqsanger.gz | |||
| SRR6781111.fastq.gz | Fastqsanger.gz | |||
| SRR6781102.fastq.gz | Fastqsanger.gz |
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Project description:Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and a determinant of neuronal number in the mammalian cortex. We find three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation. Furthermore, NOTCH2NL genes provide the breakpoints in typical cases of 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism, and deletions with microcephaly and schizophrenia. Thus, the emergence of hominin-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger hominin neocortex accompanied by loss of genomic stability at the 1q21.1 locus and a resulting recurrent neurodevelopmental disorder.
2018-02-26 | GSE111082 | GEO
Project description:The human cerebral cortex has undergone rapid expansion and increased complexity during recent evolution. Hominid-specific gene duplications represent a major driving force of evolution, but their impact on human brain evolution remains unclear. Using tailored RNA sequencing (RNAseq), we profiled the spatial and temporal expression of Hominid-specific duplicated (HS) genes in the human fetal cortex, leading to the identification of a repertoire of 36 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among these we focused on NOTCH2NL, previously uncharacterized HS paralogs of NOTCH2. NOTCH2NL promote the clonal expansion of human cortical progenitors by increasing self-renewal, ultimately leading to higher neuronal output. NOTCH2NL function by activating the Notch pathway, through inhibition of Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes linking genomic evolution to human brain development, and reveals how hominin-specific NOTCH paralogs may have contributed to the expansion of the human cortex.
The dataset contains raw sequences (FASTQ files) from the Illumina 2x150bp paired-end RNA sequencing profiles of 11 fetal human brain samples at 7, 9, 12, 15 and 21 gestational weeks.
| EGAS00001002798 | EGA
Project description:Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders.
| S-EPMC5986104 | biostudies-literature
Project description:Ogt catalyzed O-linked N-acetylglucosamine (O-GlcNAcylation, O-GlcNAc) plays an important function in diverse biological processes and diseases. However, the roles of Ogt in regulating neurogenesis remain largely unknown. Here, we show that Ogt deficiency or depletion in adult neural stem cells (aNSCs) leads to the diminishment of aNSCs pool and the aberrant neurogenesis, and consequently impairs cognitive function of adult mice. RNA sequencing reveals that Ogt deficiency alters the transcription of genes relating to cell cycle, neurogenesis, and neuronal development. Mechanistic studies show that Ogt directly interacts with Notch1 and catalyzes the O-GlcNAc modification of Notch TM/ICD fragment. The decreased O-GlcNAc modification of TM/ICD increases the binding of E3 ubiquitin ligase Itch to TM/ICD and promotes its degradation. Itch knockdown rescues neurogenic defects in Ogt-deficient mice. OGT also regulates human cortical neurogenesis in forebrain organoids derived from induced pluripotent stem cells. Our findings reveal the essential roles and mechanisms of Ogt and O-GlcNAc modification in regulating mammalian neurogenesis and cognition.
2020-12-15 | GSE163141 | GEO
Project description:During cortical development, radial glial cells, known as neural stem cells, initially generate a large number of cortical glutamatergic pyramidal neurons through a process called neurogenesis. This is followed by the generation of a diversity of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, known as gliogenesis. However, the molecular mechanisms underlying the switch from cortical neurogenesis to gliogenesis, and the subsequent fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, remain unclear. Here, we report that extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting cortical gliogenesis and the generation of cortical glial progenitors. Additionally, SHH-SMO-GLI activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that NOTCH signaling is absolutely required for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is crucial for the fate determination of olfactory bulb interneurons from cortical progenitors. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.
2024-08-23 | GSE274547 | GEO
Project description:Postnatal brain neurogenesis in mammals is believed to be restricted to rare germinative remnants of the neuroepithelium. In this study, we discovered that, in the postnatal brain, a subset of embryonically derived progenitors is present in meningeal substructures. These cells migrate from the meningeal substructures to the retrosplenial and visual motor cortex and differentiate into (electrically) functional integrated neurons. Lineage tracing analysis revealed that this subset of neural progenitors originate largely from PDGFR+ cells. PDGFR-derived cells differentiate mostly into Satb2+ neurons in cortical layers I-IV. Thus, a reservoir of embryonically derived progenitors in the meninges contributes to postnatal cerebral cortical neurogenesis.
2016-11-23 | E-MTAB-4951 | biostudies-arrayexpress
Project description:During cortical development, radial glial cells, known as neural stem cells, initially generate a large number of cortical glutamatergic pyramidal neurons through a process called neurogenesis. This is followed by the generation of a diversity of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, known as gliogenesis. However, the molecular mechanisms underlying the switch from cortical neurogenesis to gliogenesis, and the subsequent fate determination of cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons, remain unclear. Here, we report that extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting cortical gliogenesis and the generation of cortical glial progenitors. Additionally, SHH-SMO-GLI activator signaling has an auxiliary function to ERK during these processes. We further demonstrate that NOTCH signaling is absolutely required for the fate determination of astrocytes, while ERK signaling plays a prominent role in oligodendrocyte fate specification, and SHH signaling is crucial for the fate determination of olfactory bulb interneurons from cortical progenitors. We provide evidence suggesting that this mechanism is conserved in both mice and humans. Finally, we propose a unifying principle of mammalian cortical gliogenesis.
2024-08-21 | GSE275004 | GEO
Project description:The human cerebral cortex underwent rapid enlargement and complexification during recent evolution. Hominid-specific (HS) genes arising from genomic duplications may be involved, but it remains unclear how much and which HS genes contribute to human brain development. Using tailored RNAseq profiling, we identify a repertoire of >60 HS genes that display robust and dynamic expression during human fetal corticogenesis. Among these, Notch2NL genes stood out as human-specific Notch2 paralogs that promotes cortical progenitor maintenance. Clonal analyses of human cortical progenitors revealed that Notch2NL promotes their expansion by increasing self-renewal, ultimately leading to higher clonal neuronal output. Notch2NL acts by direct activation of the Notch pathway, through cell-autonomous inhibition of Delta/Notch interactions. Our data identify a large repertoire of newly evolved genes linking human brain development and evolution, and indicate how human-specific Notch paralogs may have contributed to the expansion of the human brain.
2018-04-06 | E-MTAB-6232 | biostudies-arrayexpress
Project description:During cortical development neurons are generated sequentially from basal progenitors (BPs) which specifically express the transcription factor Tbr2. We used fluorescent-activaed cell sorting (FACS) to isolate BPs from Tbr2GFP knockin reporter mice (Arnold SJ et al. Genesis, 2009) at early (embryonic day, E13) and late (embryonic day, E16) stages of cortical neurogenesis and determined mRNA expression profiles using mouse mRNA microarray (Illumina MouseWG-6 v2). Comparison of E13 and E16 mRNA expression profiles allowed us to identify regulatory gene networks for maintaining stage specific homeostasis of BPs throughout neurogenesis. FACS isolated BPs at E13 and E16 mouse brain cortex were used for microarray analyses. Six biological replicates (embryonic cortex from three different litters) for E13 and five biological replicates (embryonic cortex from three different litters) for E16 were analysed.
2014-05-01 | E-GEOD-45450 | biostudies-arrayexpress
Project description:Meningeal cells contribute to postnatal cortical neurogenesis.
| PRJEB14890 | ENA