The conserved nuclear receptor Ftz‐F1 is required for embryogenesis, moulting and reproduction in Caenorhabditis elegans

Asahina, Masako; Ishihara, Takeshi; Jindra, Marek; Kohara, Yuji; Izui, Katsura; Hirose, Susumu

doi:10.1046/j.1365-2443.2000.00361.x

Cited by 101 publications

(101 citation statements)

References 65 publications

(59 reference statements)

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“…Interestingly, inhibition of nhr-23, nhr-25, and lrp-1 gene expression also resulted in some morphological abnormalities. All these genes, including cpz-1, are highly expressed in the major hypodermal cells in all larval stages of nematodes, which supports their involvement in epidermal differentiation during or after molting (45,46,48).…”

Section: Discussionmentioning

confidence: 60%

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The Caenorhabditis elegans Cathepsin Z-like Cysteine Protease, Ce-CPZ-1, Has a Multifunctional Role during the Worms' Development

Hashmi¹,

Zhang²,

Oksov

et al. 2004

Journal of Biological Chemistry

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We have analyzed the expression and function of Cecpz-1, a Caenorhabditis elegans cathepsin Z-like cysteine protease gene, during development of the worm. The cpz-1 gene is expressed in various hypodermal cells of all developmental stages and is specifically expressed in the gonads and the pharynx of adult worms. Disruption of cpz-1 function by RNA interference or cpz-1(ok497) deletion mutant suggests that cpz-1 has a role in the molting pathways. The presence of the native CPZ-1 protein in the hypodermis/cuticle of larval and adult stages and along the length of the pharynx of adult worms, as well as the cyclic expression of the transcript during larval development, supports such function. We hypothesize that the CPZ-1 enzyme functions directly as a proteolytic enzyme degrading cuticular proteins before ecdysis and/or indirectly by processing other proteins such as proenzymes and/or other proteins that have an essential role during molting. Notably, an impressive level of the CPZ-1 native protein is present in both the new and the old cuticles during larval molting, in particular in the regions that are degraded prior to shedding and ecdysis. The similar localization of the related Onchocerca volvulus cathepsin Z protein suggests that the function of CPZ-1 during molting might be conserved in other nematodes. Based on the cpz-1 RNA interference and cpz-1 (ok497) deletion mutant phenotypes, it appears that cpz-1 have additional roles during morphogenesis. Deletion of cpz-1 coding sequence or inhibition of cpz-1 function by RNA interference also caused morphological defects in the head or tail region of larvae, improperly developed gonad in adult worms and embryonic lethality. The CPZ-1 native protein in these affected regions may have a role in the cuticular and the basement membrane extracellular matrix assembly process. The present findings have defined a critical role for cathepsin Z in nematode biology.Based on the identification and characterization of a cysteine protease in human brain, a new subfamily of cysteine proteases of the papain family, the cathepsin Z-like enzyme, was recently classified (1). The human brain cathepsin Z was, however, found to be widely expressed in many tissues, suggesting that this enzyme is possibly involved in the normal intracellular protein degradation that takes place in all cell types. Notably, the enzyme was also found in many cancer cell lines and in primary tumors from different sources, which also suggested a role for this enzyme in tumor progression (1). The human cathepsin Z contains distinctive features that separate it from other human cysteine proteases (2). Cathepsin Z is characterized by an unusual and unique 3-amino acid insertion (HIP) in the highly conserved region between the glutamine of the putative oxyanion hole and the active site cysteine, which might confer special properties to the enzyme (3). It functional diversity is generated by the addition of the HIP residues including His 23 in the mature enzyme that provides an anchor for the C terminus of a s...

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Section: Discussionmentioning

confidence: 60%

“…Control mechanisms that regulate such a complicated process are poorly understood, but recent studies have implicated two C. elegans nuclear hormone receptors (NHR-23 and NHR-25) in the regulation of molting (45)(46)(47). Molting defects were observed after interference with C. elegans nhr-25 gene expression by RNAi.…”

Section: Discussionmentioning

confidence: 99%

The Caenorhabditis elegans Cathepsin Z-like Cysteine Protease, Ce-CPZ-1, Has a Multifunctional Role during the Worms' Development

Hashmi¹,

Zhang²,

Oksov

et al. 2004

Journal of Biological Chemistry

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“…The nhr-25 gene encodes an orphan nuclear receptor in C. elegans, and loss of function by using microinjection of dsRNA into adult hermaphrodites results in progeny with molting and other defects (17,18). The Drosophila homologue of nhr-25 is ␤FTZ-F1.…”

Section: Gene Expression In Chr3 (Nhr-23) Rnaimentioning

confidence: 99%

“…Of the 270 C. elegans NHRs, only 15 are obvious orthologs of the NHRs of vertebrates or Drosophila; the rest of the C. elegans NHRs are probably nematode-specific. Studies of several of the C. elegans NHRs demonstrated a role for these factors in larval development [daf-12 (12)], neural development [nhr-55 (13) and fax-1 (14)], sex determination [nhr-24͞sex-1 (15)], and molting [nhr-23 (CHR3) (16) and nhr-25 (17,18)]. …”

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confidence: 99%

Nuclear hormone receptor CHR3 is a critical regulator of all four larval molts of the nematodeCaenorhabditis elegans

Kostrouchová

Krause

Kostrouch

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

117

136

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CHR3 (nhr-23, NF1F4), the homologue of Drosophila DHR3 and mammalian ROR͞RZR͞RevErbA nuclear hormone receptors, is important for proper epidermal development and molting in the nematode Caenorhabditis elegans. Disruption of CHR3 (nhr-23) function leads to developmental changes, including incomplete molting and a short, fat (dumpy) phenotype. Here, we studied the role of CHR3 during larval development by using expression assays and RNA-mediated interference. We show that the levels of expression of CHR3 (nhr-23) cycle during larval development and reduction of CHR3 function during each intermolt period result in defects at all subsequent molts. Assaying candidate gene expression in populations of animals treated with CHR3 (nhr-23) RNAmediated interference has identified dpy-7 as a potential gene acting downstream of CHR3. These results define CHR3 as a critical regulator of all C. elegans molts and begin to define the molecular pathway for its function.molting ͉ development N uclear hormone receptors (NHRs) form a large superfamily of transcription factors that are important for the regulation of cell metabolism, development, and reproduction (1-3). The typical receptor consists of six domains. The most conserved domain is the DNA-binding domain (DBD) and is characteristic for the NHR superfamily. It is formed by two zinc finger motifs that are conserved through evolution (4-6). A second, less conserved domain is the ligand-binding domain, located in the C terminus of the molecule and involved in binding of small hydrophobic molecules, hormones of the steroid class, thyroid hormone, retinoic acid stereoisomers, farnesoids, prostaglandins, and terpenoids (2). The generally accepted classification of NHRs is based on homology in both the DBD and the ligandbinding domain and the specific ligands (if known), which activate the receptors. The majority of NHRs have no known ligands and usually are referred to as orphan receptors.The NHRs are present in a majority of Metazoan species higher than diploblasts. NHRs apparently evolved from a single gene present in a Metazoan ancestor before the divergence of diploblastic species (4-6). There are about 70 NHRs in vertebrates, 22 in Drosophila We previously have cloned the C. elegans orphan NHR CHR3 (19), which is a homologue of Drosophila DHR3 (20), Manduca sexta MHR3 (21), and mammalian ROR͞RZR͞Rev ErbA (22, 23). For clarity, we refer to it in this paper by using both its common and gene names, CHR3 (nhr-23). The gene is classified as NR1F4 in a unified nomenclature system for the NHR superfamily (24). We previously showed that CHR3 (nhr-23) is expressed in the epidermis of C. elegans throughout development and that it was required for proper molting (16).Molting is a complex of developmental processes characteristic for a clad Ecdysozoa, which includes arthropods, tardigrades, onychophorans, nematodes, nematomorphs, kinorhynchs, and priapulids (25). At each molt, there is production of the new outer-body cover, the exoskeleton, and the old part is shed. Molting represents...

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“…So far, the regulatory mechanisms of C. elegans molting are not yet understood, although about a dozen genes have been identified that lead to molting defects when mutated. These genes can be classified into five categories based on their possible functions: (1) proteases that are used to degrade the old cuticle, including a cathepsin Z-like cysteine protease (Cecpz-1) (Hashmi et al, 2004), and two metalloproteases, nas-36 and nas-37 (Davis et al, 2004;Suzuki et al, 2004); (2) transcriptional regulators, including nhr-23 (Kostrouchova et al, 1998(Kostrouchova et al, , 2001, nhr-25 (Asahina et al, 2000;Gissendanner and Sluder, 2000), and let-19 (Wang et al, 2004); (3) enzymes involved in cholesterol metabolism such as let-767 (Kuervers et al, 2003) or cholesterol transporters such as lrp-1 (Yochem et al, 1999); (4) molecules involved in secretion and extracellular transport such as sec-23 (Roberts et al, 2003) and CeVps-27 (Roudier et al, 2005); (5) others, such as the angiotensin converting enzyme-like non-peptidase acn-1 (Brooks et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Thehedgehog-related genequa-1 is required for molting inCaenorhabditis elegans

et al. 2006

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The Caenorhabditis elegans genome encodes ten proteins that share similarity with Hedgehog through the C-terminal Hint/Hog domain. While most genes are members of larger gene families, qua-1 is a single copy gene. Here we show that orthologs of qua-1 exist in many nematodes, including Brugia malayi, which shared a common ancestor with C. elegans about 300 million years ago. The QUA-1 proteins contain an N-terminal domain, the Qua domain, that is highly conserved, but whose molecular function is not known. We have studied the expression pattern of qua-1 in C. elegans using a qua-1::GFP transcriptional fusion. qua-1 is mainly expressed in hyp1 to hyp11 hypodermal cells, but not in seam cells. It is also expressed in intestinal and rectal cells, sensilla support cells, and the P cell lineage in L1. The expression of qua-1::GFP undergoes cyclical changes during development in phase with the molting cycle. It accumulates prior to molting and disappears between molts. Disruption of the qua-1 gene function through an internal deletion that causes a frame shift with premature stop in the middle of the gene results in strong lethality. The animals arrest in the early larval stages due to defects in molting. Electron microscopy reveals double cuticles due to defective ecdysis, but no obvious defects are seen in the hypodermis. Qua domain-only::GFP and full-length QUA-1::GFP fusion constructs are secreted and associated with the overlying cuticle, but only QUA-1::GFP rescues the mutant phenotype. Our results suggest that both the Hint/Hog domain and Qua domain are critically required for the function of QUA-1.

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The conserved nuclear receptor Ftz‐F1 is required for embryogenesis, moulting and reproduction in Caenorhabditis elegans

Cited by 101 publications

References 65 publications

The Caenorhabditis elegans Cathepsin Z-like Cysteine Protease, Ce-CPZ-1, Has a Multifunctional Role during the Worms' Development

The Caenorhabditis elegans Cathepsin Z-like Cysteine Protease, Ce-CPZ-1, Has a Multifunctional Role during the Worms' Development

Nuclear hormone receptor CHR3 is a critical regulator of all four larval molts of the nematodeCaenorhabditis elegans

Thehedgehog-related genequa-1 is required for molting inCaenorhabditis elegans

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