NHR-40, a Caenorhabditis elegans supplementary nuclear receptor, regulates embryonic and early larval development.

Nuclear hormone receptors (NHRs) are important regulators of development and metabolism in animal species. They are characterized by the ability to regulate gene expression in response to the binding of small hydrophobic molecules, hormones, metabolites, and xenobiotics. The Caenorhabditis elegans genome contains 284 sequences that share homology to vertebrate and insect NHRs, a surprisingly large number compared with other species. The majority of C. elegans NHRs are nematode-specific and are referred to as supplementary nuclear receptors (supnrs) that are thought to have originated by duplications of an ancient homolog of vertebrate HNF4. Here, we report on the function of NHR-40, a member of a subgroup of 18 Caenorhabditis elegans supnrs that share DNA-binding domain sequence CNGCKT. NHR-40 is expressed from at least two promoters, generates at least three transcripts, and is detectable in pharyngeal, body wall, and sex muscles as well as in a subset of neurons. The downregulation of nhr-40 by RNAi, or a mutant with an intronic region deletion, results in late embryonic and early larval arrest with defects in elongation and morphogenesis. The nhr-40 loss of function phenotype includes irregular development of body wall muscle cells and impaired movement and coordination resembling neuromuscular affection. NHR-40 joins the list of C. elegans NHRs that regulate development and suggests that members of extensive nematode supnr family have acquired varied and novel functions during evolution.

BIR-1, a Caenorhabditis elegans homologue of Survivin, regulates transcription and development.

bir-1, a Caenorhabditis elegans inhibitor-of-apoptosis gene homologous to Survivin is organized in an operon with the transcription cofactor C. elegans SKIP (skp-1). Because genes arranged in operons are frequently linked functionally, we have asked whether BIR-1 also functions in transcription. bir-1 inhibition resulted in multiple developmental defects that overlapped with C. elegans SKIP loss-of-function phenotypes: retention of eggs, dumpy, movement defects, and lethality. bir-1 RNA-mediated interference decreased expression of several gfp transgenes and the endogenous genes dpy-7 and hlh-1. Immunoblot analysis revealed decreased phosphoacetylated histones in bir-1 RNA-mediated interference-treated worms. In a heterologous transfection system, BIR-1 augments thyroid hormone-regulated transcription and has an additive effect with SKIP. These results show that BIR-1 functions in the regulation of transcription and development.

SKIP is an indispensable factor for Caenorhabditis elegans development.

SKI-binding protein (SKIP) is a transcription cofactor present in all eukaryotes. Here we show that SKIP is a unique protein that is required for Caenorhabditis elegans viability and development. Expression of CeSKIP (skp-1) assayed by RT-PCR and by GFP fluorescence in transgenic lines starts in embryos and continues to adulthood. Loss of CeSKIP activity by RNA-mediated inhibition results in early embryonic arrest similar to that seen following inhibition of RNA polymerase II. RNA polymerase II phosphorylation appears normal early in CeSKIP RNA-mediated inhibition treated embryos although the expression of several embryonic GFP reporter genes is severely restricted or absent. Our data suggest that CeSKIP is an essential component of many RNA polymerase II transcription complexes and is indispensable for C. elegans development.