NHR-23 dependent collagen and hedgehog-related genes required for molting

Abstract

NHR-23, a conserved member of the nuclear receptor family of transcription factors, is required for normal development in C. elegans where it plays a critical role in growth and molting. In a search for NHR-23 dependent genes, we performed whole genome comparative expression microarrays on both control and nhr-23 inhibited synchronized larvae. Genes that decreased in response to nhr-23 RNAi included several collagen genes. Unexpectedly, several hedgehog-related genes were also down-regulated after nhr-23 RNAi. A homozygous nhr-23 deletion allele was used to confirm the RNAi knockdown phenotypes and the changes in gene expression. Our results indicate that NHR-23 is a critical co-regulator of functionally linked genes involved in growth and molting and reveal evolutionary parallels among the ecdysozoa.

Conserved Ankyrin Repeat Proteins and Their NIMA Kinase Partners Regulate Extracellular Matrix Remodeling and Intracellular Trafficking inCaenorhabditis elegans

“…Positive regulators of molting include matrix metalloproteases (Davis et al 2004;Hashmi et al 2004;Suzuki et al 2004;Altincicek et al 2010;Kim et al 2011;Stepek et al 2011), which are important for digestion of the old cuticle or processing of the new cuticle precursors, as well as selenoproteins, which promote collagen cross-linking (Stenvall et al 2011). Other functional classes of molecules critical for molting include sterol-binding nuclear hormone receptors (NHRs) (Kostrouchova et al 1998(Kostrouchova et al , 2001Gissendanner and Sluder 2000;Hayes et al 2006;Monsalve and Frand 2012), enzymes controlling sterol and fatty acid synthesis (Jia et al 2002;Kuervers et al 2003;Entchev and Kurzchalia 2005;Li and Paik 2011), and hedgehog-related proteins (Zugasti et al 2005;Hao et al 2006), which are often modified by sterols (Wendler et al 2006) and are dependent on NHRs for expression (Kouns et al 2011). Accordingly, dietary cholesterol promotes normal molting (Yochem et al 1999;Merris et al 2003;Entchev and Kurzchalia 2005;Roudier et al 2005), along with the LRP-1/megalin lipoprotein receptor, which is thought to support lipid uptake by the epidermis (Yochem et al 1999;May et al 2007).…”

Nuclear receptors in nematode development: Natural experiments made by a phylum

“…In seam cells, nhr-60 expression is dependent on NHR-23. Another member of the NR family, NHR-91 is dependent on NHR-23 expression as identified by whole genome expressional microarrays [143] (and was confirmed by qPCR, unpublished).…”

“…Interestingly, the NR6 subfamily member GCNF homologues in nematodes and insects are part of the cascade. NHR-91, the nematode orthologue of GCNF is downstream of NHR-23 [143], and in insects HR4 is a negative regulator transmitting the negative regulation upstream of HR3 [145,146]. GCNF is widely expressed in vertebrate tissues, similarly as RORs and it is therefore likely that such interplay is employed in various tissues.…”

“…Downstream of NHR-23 are collagen genes, enzymes and genes likely to regulate development such as the hedgehog related genes (Hh-r) and several NRs [140,142,143].…”

The Caenorhabditis elegans Excretory System: A Model for Tubulogenesis, Cell Fate Specification, and Plasticity

“…V. Sundaram, unpublished data). In the epidermis, NHR-23 and NHR-25 are required for cyclical expression of collagens and other secreted ECM factors, and for proper molting (Gissendanner and Sluder 2000;Hayes et al 2006;Kouns et al 2011). These transcription factors are likely to play similar roles in the duct and pore.…”