ABSTRACT
The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.
Subject(s)
Humans , Autism Spectrum Disorder/metabolism , Cell Movement/genetics , Interneurons/metabolism , Neurodevelopmental Disorders/genetics , Neurons/metabolism , Rho Guanine Nucleotide Exchange Factors/geneticsABSTRACT
Los problemas médicos gastrointestinales, nutricionales, metabólicos, endocrinológicos y de microbiota en los pacientes pediátricos con diagnóstico de trastorno del espectro autista (TEA) son parte de los problemas médicos concomitantes al diagnóstico. La prevalencia alcanza a más del 91 % en el caso de los problemas gastrointestinales, hasta el 89 % para los nutricionales y metabólicos, más del 50 % de disfunción tiroidea y hasta el 100 % para los relacionados con la microbiota.Es urgente actualizar la práctica médica para incluir la evaluación, testeo, diagnóstico y tratamiento de estos problemas médicos concomitantes al diagnóstico de TEA en la población pediátrica, adolescente y adulta. El tratamiento riguroso de dichos problemas genera cambios positivos en la calidad de vida y en la sintomatología bajo la cual el TEA se diagnostica en muchos casos. Debe basarse en evidencia científica de alta calidad, con control y cuidado médico adecuado
Gastrointestinal, nutritional, metabolic, endocrine, and microbiota medical problems in pediatric patients diagnosed with autism spectrum disorder (ASD) are some of the coexisting medical conditions in ASD diagnosis. Their prevalence reaches more than 91 % for gastrointestinal problems, up to 89 % for nutritional and metabolic disorders, more than 50 % for thyroid dysfunction, and up to 100 % for microbiota-related conditions.There is an urgency for medical practice to be updated and to include the assessment, testing, diagnosis, and treatment of these coexisting medical conditions in ASD diagnosis in the pediatric, adolescent, and adult population. A strict management of such conditions results in positive changes in the quality of life and symptoms based on which ASD is diagnosed many times. It should be based on high-quality scientific evidence with an adequate medical care and control
Subject(s)
Humans , Child, Preschool , Child , Adolescent , Endocrine System Diseases/metabolism , Microbiota , Autism Spectrum Disorder/microbiology , Gastrointestinal Diseases/metabolism , Concurrent Symptoms , Nutritional Status , Autism Spectrum Disorder/complications , Autism Spectrum Disorder/diet therapy , Autism Spectrum Disorder/metabolism , Gastrointestinal Diseases/complications , Gastrointestinal Diseases/diet therapyABSTRACT
Autism spectrum disorders (ASDs) are characterized by deficits in the individual’s ability to socialize, communicate, and use the imagination, in addition to stereotyped behaviors. These disorders have a heterogenous phenotype, both in relation to symptoms and regarding severity. Organic problems related to the gastrointestinal tract are often associated with ASD, including dysbiosis, inflammatory bowel disease, exocrine pancreatic insufficiency, celiac disease, indigestion, malabsorption, food intolerance, and food allergies, leading to vitamin deficiencies and malnutrition. In an attempt to explain the pathophysiology involved in autism, a theory founded on opioid excess has been the focus of various investigations, since it partially explains the symptomatology of the disorder. Another hypothesis has been put forward whereby the probable triggers of ASDs would be related to the presence of bacteria in the bowel, oxidative stress, and intestinal permeability. The present update reviews these hypotheses.