The zebrafish kohtalo/trap230 gene is required for the development of the brain, neural crest, and pronephric kidney

Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2006; 102(51):18473-8. DOI: 10.1073/pnas.0509457102
Source: PubMed

ABSTRACT Mutation of the gene encoding the Mediator component thyroid hormone receptor-associated protein (TRAP)230/MED12 affects the development of multiple systems in zebrafish embryogenesis. We isolated two ethylnitrosourea-induced alleles in the gene encoding this protein and named the locus kohtalo (kto) after the homologous locus in Drosophila. Homozygous kto mutant zebrafish embryos show defects in brain, neural crest, and kidney development and die at approximately 6 days postfertilization. In the affected tissues, differentiation is initiated and many cell type-specific genes are expressed, but there is a failure of morphogenesis and failure to complete differentiation. These results suggest that critical targets of TRAP230 function may include proteins important for cell mobility, cell sorting, and tissue assembly.

5 Reads
  • Source
    • "In addition to CDK8 and CCNC, MED12 and MED13 are also critical regulators of developmental gene expression programs (Hong et al., 2005; Kennison & Tamkun, 1988; Rau et al., 2006; Wang et al., 2006). In a C. elegans RNAi screen, Med12 (dpy-22) was identified by the Fraser lab as a highly connected ''hub'' gene that regulated numerous signaling pathways (Lehner et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.
    Critical Reviews in Biochemistry and Molecular Biology 10/2013; 48(6). DOI:10.3109/10409238.2013.840259 · 7.71 Impact Factor
  • Source
    • "Not surprisingly, the sox9a/sox9b double mutant displayed severe craniofacial abnormalities. Zebrafish mutants in Trap230/Med12, a transcriptional co-activator for Sox9, were characterized by disrupted cartilage development [40], [41]. Furthermore, knockdown experiments showed that runx2b and runx3 are critically involved in chondrogenesis: runx2b morphants lack the entire pharyngeal skeleton whereas only rudimentary trabeculae are formed in runx3 morphants [42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycomb group (PcG) genes are chromatin modifiers that mediate epigenetic silencing of target genes. PcG-mediated epigenetic silencing is implicated in embryonic development, stem cell plasticity, cell fate maintenance, cellular differentiation and cancer. However, analysis of the roles of PcG proteins in maintaining differentiation programs during vertebrate embryogenesis has been hampered due to the early embryonic lethality of several PcG knock-outs in the mouse. Here, we show that zebrafish Ring1b/Rnf2, the single E3 ubiquitin ligase in the Polycomb Repressive Complex 1, critically regulates the developmental program of craniofacial cell lineages. Zebrafish ring1b mutants display a severe craniofacial phenotype, which includes an almost complete absence of all cranial cartilage, bone and musculature. We show that Cranial Neural Crest (CNC)-derived cartilage precursors migrate correctly into the pharyngeal arches, but fail to differentiate into chondrocytes. This phenotype is specific for cartilage precursors, since other neural crest-derived cell lineages, including glia, neurons and chromatophores, are formed normally in ring1b mutants. Our results therefore reveal a critical and specific role for Ring1b in promoting the differentiation of cranial neural crest cells into chondrocytes. The molecular mechanisms underlying the pathogenesis of craniofacial abnormalities, which are among the most common genetic birth defects in humans, remain poorly understood. The zebrafish ring1b mutant provides a molecular model for investigating these mechanisms and may lead to the discovery of new treatments or preventions of craniofacial abnormalities.
    PLoS ONE 09/2013; 8(9):e73997. DOI:10.1371/journal.pone.0073997 · 3.23 Impact Factor
  • Source
    • "Notably, MED12 is required for normal neuronal development in zebrafish, most likely by acting as a coactivator of the transcription factor Sox9; as in our study, some, but not all neurons were affected by med12 mutations (Hong et al., 2005; Wang et al., 2006). In Drosophila cdk8 mutants were isolated in genetic screens for wiring defects in the visual system (Berger et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Receptors expressed on the growth cone of outgrowing axons detect cues required for proper navigation. The pathway choices available to an axon are in part defined by the set of guidance receptors present on the growth cone. Regulated expression of receptors and genes controlling the localization and activity of receptors ensures that axons respond only to guidance cues relevant for reaching their targets. In genetic screens for axon guidance mutants, we isolated an allele of let-19/mdt-13, a component of the Mediator, a large ∼30 subunit protein complex essential for gene transcription by RNA polymerase II. LET-19/MDT-13 is part of the CDK8 module of the Mediator. By testing other Mediator components, we found that all subunits of the CDK8 module as well as some other Mediator components are required for specific axon navigation decisions in a subset of neurons. Expression profiling demonstrated that let-19/mdt-13 regulates the expression of a large number of genes in interneurons. A mutation in the sax-3 gene, encoding a receptor for the repulsive guidance cue SLT-1, suppresses the commissure navigation defects found in cdk-8 mutants. This suggests that the CDK8 module specifically represses the SAX-3/ROBO pathway to ensure proper commissure navigation.
    Developmental Biology 02/2013; 377(2). DOI:10.1016/j.ydbio.2013.02.009 · 3.55 Impact Factor
Show more


5 Reads
Available from