RESUMO
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.
Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/crescimento & desenvolvimento , Estrogênios/fisiologia , Neurogênese , Animais , Transtorno do Espectro Autista/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Avaliação Pré-Clínica de Medicamentos , Estrogênios/administração & dosagem , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Fatores de Risco , Transdução de Sinais , XenopusRESUMO
Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3ß inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD.
Assuntos
Espinhas Dendríticas/metabolismo , Proteínas com Domínio T/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/metabolismo , Espinhas Dendríticas/fisiologia , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Sinapses/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/fisiologia , Tálamo/metabolismo , Via de Sinalização Wnt/genéticaRESUMO
Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.
Assuntos
Transtorno Autístico/tratamento farmacológico , Estrogênios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Animais , Animais Geneticamente Modificados , Transtorno Autístico/genética , Modelos Animais de Doenças , Estrogênios/uso terapêutico , Genisteína/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Larva , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Fenótipo , Fitoestrógenos/farmacologia , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/genética , Transtornos da Transição Sono-Vigília/tratamento farmacológico , Transtornos da Transição Sono-Vigília/genética , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Peixe-ZebraRESUMO
Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.