title: A subunit of the mediator complex regulates vertebrate neuronal development.
abstract: The unique profiles of gene expression dictate distinct cellular identity. How these profiles are established during development is not clear. Here we report that the mutant motionless (mot), identified in a genetic screen for mutations that affect neuronal development in zebrafish, displays deficits of monoaminergic neurons and cranial sensory ganglia, whereas expression of the pan-neuronal marker Hu is largely unperturbed; GABAergic and subsets of cranial motor neurons do not appear to be deficient. Positional cloning reveals that mot encodes Med12, a component of the evolutionarily conserved Mediator complex, whose in vivo function is not well understood in vertebrates. mot/med12 transcripts are enriched in the embryonic brain and appear distinct from two other Mediator components Med17 and Med21. Delivery of human med12 RNA into zebrafish restores normality to the mot mutant and, strikingly, leads to premature neuronal differentiation and an increased production of monoaminergic neuronal subtypes in WT. Further investigation reveals that mot/med12 is necessary to regulate, and when overexpressed is capable of increasing, the expression of distinct neuronal determination genes, including zash1a and lim1, and serves as an in vivo cofactor for Sox9 in this process. Together, our analyses reveal a regulatory role of Mot/Med12 in vertebrate neuronal development.
authors.affiliation: Program in Genetics, Neuroscience, and Developmental Biology, Department of Biopharmaceutical Sciences, and Center for Human Genetics, University of California, San Francisco, CA 94143, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Etsuko
authors.initials: E
authors.lastname: Uno
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Su
authors.initials: S
authors.lastname: Guo
mesh_terms: D000818:Animals; D001483:Base Sequence; D015415:Biomarkers; D001921:Brain / Q000196:embryology / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D056892:Mediator Complex; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C468127:Ascl1a protein, zebrafish; D015415:Biomarkers; D006609:High Mobility Group Proteins; C460107:MED12 protein, human; C513481:Med12 protein, zebrafish; D056892:Mediator Complex; D021122:Protein Subunits; D011988:Receptors, Thyroid Hormone; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014157:Transcription Factors; D029961:Zebrafish Proteins