XB-ART-57754
Neuron
2021 Mar 03;1095:788-804.e8. doi: 10.1016/j.neuron.2021.01.002.
Show Gene links
Show Anatomy links
Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.
Willsey HR
,
Exner CRT
,
Xu Y
,
Everitt A
,
Sun N
,
Wang B
,
Dea J
,
Schmunk G
,
Zaltsman Y
,
Teerikorpi N
,
Kim A
,
Anderson AS
,
Shin D
,
Seyler M
,
Nowakowski TJ
,
Harland RM
,
Willsey AJ
,
State MW
.
???displayArticle.abstract???
Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.
???displayArticle.pubmedLink??? 33497602
???displayArticle.pmcLink??? PMC8132462
???displayArticle.link??? Neuron
???displayArticle.grants??? [+]
S10 OD018174 NIH HHS , R21 MH112158 NIMH NIH HHS, R35 GM127069 NIGMS NIH HHS , U01 MH115747 NIMH NIH HHS, R25 MH060482 NIMH NIH HHS, RF1 MH121268 NIMH NIH HHS
Species referenced: Xenopus tropicalis
Genes referenced: adnp ank2 arid1b chd2 chd8 dlx5 dyrk1a lhx6 nkx2-1 nrxn1 olig2 pax6 pcna pogz ptch1 scn2a shh syngap1
GO keywords: neurogenesis [+]
???displayArticle.disOnts??? autism spectrum disorder
???displayArticle.omims??? AUTISM
???displayArticle.gses??? GSE155553: Xenbase, NCBI
GSE155554:
NCBI
References [+] :
Anderson,
Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons.
1997, Pubmed
Anderson, Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. 1997, Pubmed
Ben-David, Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. 2013, Pubmed
Bernier, Disruptive CHD8 mutations define a subtype of autism early in development. 2014, Pubmed
Bhattacharya, CRISPR/Cas9: An inexpensive, efficient loss of function tool to screen human disease genes in Xenopus. 2015, Pubmed , Xenbase
Blackburn, DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract. 2019, Pubmed , Xenbase
Brinkman, Easy quantitative assessment of genome editing by sequence trace decomposition. 2014, Pubmed
Britto, A critical role for sonic hedgehog signaling in the early expansion of the developing brain. 2002, Pubmed
Chambers, Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. 2009, Pubmed
Chang, Genotype to phenotype relationships in autism spectrum disorders. 2015, Pubmed
Chen, Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. 2002, Pubmed
Chen, Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. 2013, Pubmed
Chiang, Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. 1996, Pubmed
Csöregh, Transcriptional analysis of estrogen effects in human embryonic neurons and glial cells. 2009, Pubmed
DeLay, Tissue-Specific Gene Inactivation in Xenopus laevis: Knockout of lhx1 in the Kidney with CRISPR/Cas9. 2018, Pubmed , Xenbase
Deniz, CRISPR/Cas9 F0 Screening of Congenital Heart Disease Genes in Xenopus tropicalis. 2018, Pubmed , Xenbase
De Rubeis, Synaptic, transcriptional and chromatin genes disrupted in autism. 2014, Pubmed
Dobin, STAR: ultrafast universal RNA-seq aligner. 2013, Pubmed
Duncan, Xenopus as a model organism for birth defects-Congenital heart disease and heterotaxy. 2016, Pubmed , Xenbase
Durak, Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. 2016, Pubmed
Echelard, Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. 1993, Pubmed
Edgar, Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. 2002, Pubmed
Ericson, Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube. 1995, Pubmed
Ericson, Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube. 1997, Pubmed
Etard, Tracking of Indels by DEcomposition is a Simple and Effective Method to Assess Efficiency of Guide RNAs in Zebrafish. 2017, Pubmed
Evers, Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders. 2017, Pubmed
Faheem, Molecular genetics of human primary microcephaly: an overview. 2015, Pubmed
Fuccillo, Temporal requirement for hedgehog signaling in ventral telencephalic patterning. 2004, Pubmed
Gallego Romero, A panel of induced pluripotent stem cells from chimpanzees: a resource for comparative functional genomics. 2015, Pubmed
Garfinkel, An interspecies heart-to-heart: Using Xenopus to uncover the genetic basis of congenital heart disease. 2017, Pubmed , Xenbase
Göckler, Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. 2009, Pubmed
Hammerschmidt, The world according to hedgehog. 1997, Pubmed
Harland, In situ hybridization: an improved whole-mount method for Xenopus embryos. 1991, Pubmed , Xenbase
He, Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. 2013, Pubmed
Hoffman, Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2. 2016, Pubmed
Horlbeck, Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation. 2016, Pubmed
Huang, Systematic Evaluation of Molecular Networks for Discovery of Disease Genes. 2018, Pubmed
Iossifov, De novo gene disruptions in children on the autistic spectrum. 2012, Pubmed
Iossifov, The contribution of de novo coding mutations to autism spectrum disorder. 2014, Pubmed
Ji, DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. 2015, Pubmed
Jin, Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. 2017, Pubmed
Kakebeen, Advancing genetic and genomic technologies deepen the pool for discovery in Xenopus tropicalis. 2019, Pubmed , Xenbase
Kang, Spatio-temporal transcriptome of the human brain. 2011, Pubmed
Katayama, CHD8 haploinsufficiency results in autistic-like phenotypes in mice. 2016, Pubmed
Koebernick, Molecular cloning and expression analysis of the Hedgehog receptors XPtc1 and XSmo in Xenopus laevis. 2001, Pubmed , Xenbase
Komada, Hedgehog signaling is involved in development of the neocortex. 2008, Pubmed
Kriegstein, Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. 2006, Pubmed
Krneta-Stankic, Xenopus: leaping forward in kidney organogenesis. 2017, Pubmed , Xenbase
Lasser, The Role of the Microtubule Cytoskeleton in Neurodevelopmental Disorders. 2018, Pubmed
Lewis, Reagents for developmental regulation of Hedgehog signaling. 2014, Pubmed , Xenbase
Li, Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders. 2015, Pubmed
Love, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. 2014, Pubmed
Mandegar, CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs. 2016, Pubmed
Martínez-Cerdeño, The role of intermediate progenitor cells in the evolutionary expansion of the cerebral cortex. 2006, Pubmed
Matsumoto, Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation. 2013, Pubmed
Mi, PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium. 2010, Pubmed
Miller, Transcriptional landscape of the prenatal human brain. 2014, Pubmed
Moreno-Mateos, CRISPRscan: designing highly efficient sgRNAs for CRISPR-Cas9 targeting in vivo. 2015, Pubmed , Xenbase
Morin, Sequencing and analysis of 10,967 full-length cDNA clones from Xenopus laevis and Xenopus tropicalis reveals post-tetraploidization transcriptome remodeling. 2006, Pubmed , Xenbase
Neale, Patterns and rates of exonic de novo mutations in autism spectrum disorders. 2012, Pubmed
Nieber, Comparative expression analysis of the neurogenins in Xenopus tropicalis and Xenopus laevis. 2009, Pubmed , Xenbase
Ogawa, Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. 2010, Pubmed , Xenbase
Ohkubo, Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles. 2002, Pubmed
O'Roak, Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. 2012, Pubmed
O'Roak, Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. 2012, Pubmed
Ortega, The Subventricular Zone: A Key Player in Human Neocortical Development. 2018, Pubmed
Packer, Neocortical neurogenesis and the etiology of autism spectrum disorder. 2016, Pubmed
Parikshak, Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. 2013, Pubmed
Paşca, Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. 2015, Pubmed
Pearl, Development of Xenopus resource centers: the National Xenopus Resource and the European Xenopus Resource Center. 2012, Pubmed , Xenbase
Qi, Combined small-molecule inhibition accelerates the derivation of functional cortical neurons from human pluripotent stem cells. 2017, Pubmed
Ruzzo, Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. 2019, Pubmed
Sakai, Protein interactome reveals converging molecular pathways among autism disorders. 2011, Pubmed
Sanders, De novo mutations revealed by whole-exome sequencing are strongly associated with autism. 2012, Pubmed
Sanders, Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. 2015, Pubmed
Satterstrom, Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. 2020, Pubmed
Schindelin, Fiji: an open-source platform for biological-image analysis. 2012, Pubmed
Sestan, Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder. 2018, Pubmed
Shao, Centrosome anchoring regulates progenitor properties and cortical formation. 2020, Pubmed
Shen, CHD2 is Required for Embryonic Neurogenesis in the Developing Cerebral Cortex. 2015, Pubmed
Shimamura, Inductive interactions direct early regionalization of the mouse forebrain. 1997, Pubmed
Sive, Baskets for in situ hybridization and immunohistochemistry. 2007, Pubmed
State, The conundrums of understanding genetic risks for autism spectrum disorders. 2011, Pubmed
State, Neuroscience. The emerging biology of autism spectrum disorders. 2012, Pubmed
Takase, Molecular cloning of two isoforms of Xenopus (Silurana) tropicalis estrogen receptor mRNA and their expression during development. 2007, Pubmed , Xenbase
Tanabe, Diversity and pattern in the developing spinal cord. 1996, Pubmed
Tebbenkamp, The developmental transcriptome of the human brain: implications for neurodevelopmental disorders. 2014, Pubmed
van Bon, Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. 2016, Pubmed
Wang, Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. 2020, Pubmed
Willsey, Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. 2013, Pubmed
Willsey, Katanin-like protein Katnal2 is required for ciliogenesis and brain development in Xenopus embryos. 2018, Pubmed , Xenbase
Willsey, Autism spectrum disorders: from genes to neurobiology. 2015, Pubmed
Willsey, The neurodevelopmental disorder risk gene DYRK1A is required for ciliogenesis and control of brain size in Xenopus embryos. 2020, Pubmed , Xenbase
Willsey, The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders. 2018, Pubmed , Xenbase
Wu, Estrogen receptors in Xenopus: duplicate genes, splice variants, and tissue-specific expression. 2003, Pubmed , Xenbase
Xu, Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders. 2014, Pubmed
Yasin, A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8. 2019, Pubmed
Ye, De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly. 2015, Pubmed
Zecevic, Contributions of cortical subventricular zone to the development of the human cerebral cortex. 2005, Pubmed
Zhao, Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3-deficient non-human primate. 2017, Pubmed
Zhu, Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. 2019, Pubmed