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Neuron 2021 Mar 03;1095:788-804.e8. doi: 10.1016/j.neuron.2021.01.002.
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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 .

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.

PubMed ID: 33497602
PMC ID: PMC8132462
Article link: Neuron
Grant support: [+]

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 [+]

Disease Ontology terms: autism spectrum disorder
GEO Series: 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