Nuclear cloning, epigenetic reprogramming, and cellular differentiation.
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Biomedical subjects
R Blelloch
Publications and source records attributed to R Blelloch.
The gon-1 gene is required for gonadal morphogenesis in Caenorhabditis elegans.
In wild-type Caenorhabditis elegans, the gonad is a complex epithelial tube that consists of long arms composed predominantly of germline tissue as well as somatic structures specialized for particular reproductive functions. In gon-1 mutants, the adult gonad is severely disorganized with essentially no arm extension and no recognizable somatic structure. The developmental defects in gon-1 mutants are limited to the gonad; other cells, tissues, and organs appear to develop normally. Previous work defined the regulatory "leader" cells as crucial for extension of the gonadal arms (J. E. Kimble and J. G. White, 1981, Dev. Biol. 81, 208-219). In gon-1 mutants, the leader cells are specified correctly, but they fail to migrate and gonadal arms are not generated. In addition, gon-1 is required for morphogenesis of the gonadal somatic structures. This second role appears to be independent of that required for leader migration. Parallel studies have shown that gon-1 encodes a secreted metalloprotease (R. Blelloch and J. Kimble, 1999, Nature 399, 586-590). We discuss how a metalloprotease may control two aspects of gonadal morphogenesis.
Animals↗
Control of organ shape by a secreted metalloprotease in the nematode Caenorhabditis elegans.
The molecular controls governing organ shape are poorly understood. In the nematode Caenorhabditis elegans, the gonad acquires a U-shape by the directed migration of a specialized 'leader' cell, which is located at the tip of the growing gonadal 'arm'. The gon-1 gene is essential for gonadal morphogenesis: in gon-1 mutants, no arm elongation occurs and somatic gonadal structures are severely malformed. Here we report that gon-1 encodes a secreted protein with a metalloprotease domain and multiple thrombospondin type-1-like repeats. This motif architecture is typical of a small family of genes that include bovine procollagen I N-protease (P1NP), which cleaves collagen, and murine ADAMTS-1, the expression of which correlates with tumour cell progression. We find that gon-1 is expressed in two sites, leader cells and muscle, and that expression in each site has a unique role in forming the gonad. We speculate that GON-1 controls morphogenesis by remodelling basement membranes and that regulation of its activity is crucial for achieving organ shape.
Amino Acid Sequence↗
Control of cell migration during Caenorhabditis elegans development.
In Caenorhabditis elegans, cell migration is guided by localized cues, including molecules such as EGL-17/FGF and UNC-6/netrin. These external cues are linked to an intracellular response to migrate, at least in part, by CED-5, a homolog of DOCK180/MBC, and MIG-2, a Rac-like GTPase. In addition, metalloproteases are required for a cell migration that controls organ shape.
Animals↗
Roles of the RAM and ANK domains in signaling by the C. elegans GLP-1 receptor.
In Caenorhabditis elegans, the GLP-1 receptor acts with a downstream transcriptional regulator, LAG-1, to mediate intercellular signaling. GLP-1 and LAG-1 are homologs of Drosophila Notch and Su(H) respectively. Here, we investigate the functions of two regions of the GLP-1 intracellular domain: the ANK repeat domain, which includes six cdc10/ankyrin repeats plus flanking amino acids, and the RAM domain, which spans approximately 60 amino acids just inside the transmembrane domain. First, we demonstrate that both ANK and RAM domains interact with the LAG-1 transcription factor. The interaction between the ANK domain and LAG-1 is only observed in nematodes by a co-localization assay and, therefore, may be either direct or indirect. By contrast, the interaction between the RAM domain and LAG-1 is likely to be direct, since it is observed by co-precipitation of the proteins in vitro as well as by yeast two-hybrid experiments. Second, we demonstrate that the RAM domain, when expressed in nematodes without a functional ANK repeat domain, does not mimic the unregulated receptor in directing cell fates or interfere with signaling by endogenous components. Finally, we show in yeast that the ANK repeats are strong transcriptional activators. Furthermore, missense mutations that eliminate receptor activity also abolish transcriptional activation by the GLP-1 ANK repeats in yeast. We speculate that one possible function for the ANK repeat domain is to act as a transcriptional co-activator with LAG-1.
Amino Acid Sequence↗