title: The CDK8 Complex and Proneural Proteins Together Drive Neurogenesis from a Mesodermal Lineage.
abstract: At least some animal species can generate neurons from mesoderm or endoderm, but the underlying mechanisms remain unknown. We screened for C. elegans mutants in which the presumptive mesoderm-derived I4 neuron adopts a muscle-like cell fate. From this screen, we identified HLH-3, the C. elegans homolog of a mammalian proneural protein (Ascl1) used for in vitro neuronal reprogramming, as required for efficient I4 neurogenesis. We discovered that the CDK-8 Mediator kinase module acts together with a second proneural protein, HLH-2, and in parallel to HLH-3 to promote I4 neurogenesis. Genetic analysis revealed that CDK-8 most likely promotes I4 neurogenesis by inhibiting the CDK-7/CYH-1 (CDK7/cyclin H) kinase module of the transcription initiation factor TFIIH. Ectopic expression of HLH-2 and HLH-3 together promoted expression of neuronal features in non-neuronal cells. These findings reveal that the Mediator CDK8 kinase module can promote non-ectodermal neurogenesis and suggest that inhibiting CDK7/cyclin H might similarly promote neurogenesis.
authors.affiliation: Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Luo
authors.affiliation: Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: horvitz@mit.edu.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000196:embryology; D055495:Neurogenesis / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D056850:Cyclin-Dependent Kinase 8; C106514:HLH-2 protein, C elegans; C106515:HLH-3 protein, C elegans
keywords: CDK8; Mediator; bHLH; kinase; neurogenesis; proneural