Nicholas J. Santistevan, Colby T. Ford, Cole S. Gilsdorf, Yevgenya Grinblat
{"title":"对斑马鱼中 mecp2 功能的行为和转录组分析。","authors":"Nicholas J. Santistevan, Colby T. Ford, Cole S. Gilsdorf, Yevgenya Grinblat","doi":"10.1002/ajmg.b.32981","DOIUrl":null,"url":null,"abstract":"<p>Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse <i>Mecp2</i> mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish <i>mecp2</i> mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish <i>mecp2</i> mutants from 5 to 7 days post-fertilization (dpf). We show that zebrafish <i>mecp2</i> function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for <i>mecp2</i> in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires <i>mecp2</i> function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":1.6000,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32981","citationCount":"0","resultStr":"{\"title\":\"Behavioral and transcriptomic analyses of mecp2 function in zebrafish\",\"authors\":\"Nicholas J. Santistevan, Colby T. Ford, Cole S. Gilsdorf, Yevgenya Grinblat\",\"doi\":\"10.1002/ajmg.b.32981\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse <i>Mecp2</i> mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish <i>mecp2</i> mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish <i>mecp2</i> mutants from 5 to 7 days post-fertilization (dpf). We show that zebrafish <i>mecp2</i> function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for <i>mecp2</i> in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires <i>mecp2</i> function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.</p>\",\"PeriodicalId\":7673,\"journal\":{\"name\":\"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2024-03-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32981\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.32981\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.32981","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Behavioral and transcriptomic analyses of mecp2 function in zebrafish
Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5 to 7 days post-fertilization (dpf). We show that zebrafish mecp2 function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.
期刊介绍:
Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.