TGF-beta superfamily ligands play fundamental roles in the development and physiology of diverse animal species. Genetic and genomic analyses in the model organism Caenorhabditis elegans have ...contributed to the understanding of TGF-beta-related signal transduction mechanisms. In this chapter, I describe the currently characterized TGF-beta-related signals and signal transduction cassettes in C. elegans. Homology searches of the genome identify five TGF-beta-related genes, for which functions have been identified for three. Two of the TGF-beta-related genes, daf-7 and dbl-1, function through conventional signaling pathways. These signaling pathways are comprised of ser/thr kinase receptors, Smads, and transcription co-factors. A third TGF-beta-related gene, unc-129, functions in axonal guidance using novel signaling mechanisms. Thus, TGF-beta-related signaling in C. elegans proceeds via both conserved and novel paradigms that can inform studies in other animal systems.
In the nematode Caenorhabditis elegans, a TGFbeta-related signaling pathway regulates body size and male tail morphogenesis. We sought to identify genes encoding components or modifiers of this ...pathway in a large-scale genetic screen. Remarkably, this screen was able to identify essentially all core components of the TGFbeta signaling pathway. Among 34 Small mutants, many mutations disrupt genes encoding recognizable components of the TGFbeta pathway: DBL-1 ligand, DAF-4 type II receptor, SMA-6 type I receptor, and SMA-2, SMA-3, and SMA-4 Smads. Moreover, we find that at least 11 additional complementation groups can mutate to the Small phenotype. Four of these 11 genes, sma-9, sma-14, sma-16, and sma-20 affect male tail morphogenesis as well as body size. Two genes, sma-11 and sma-20, also influence regulation of the developmentally arrested dauer larval stage, suggesting a role in a second characterized TGFbeta pathway in C. elegans. Other genes may represent tissue-specific factors or parallel pathways for body size control. Because of the conservation of TGFbeta signaling pathways, homologs of these genes may be involved in tissue specificity and/or crosstalk of TGFbeta pathways in other animals.
In Caenorhabditis elegans, the Bone Morphogenetic Protein (BMP)-related ligand Dpp- and BMP-like-1 (DBL-1) regulates body size by promoting the larval and adult growth of the large epidermal ...syncytium hyp7 without affecting cell division. This system provides an excellent model for dissecting the growth-promoting activities of BMP ligands, since in this context the growth and differentiation functions of DBL-1 are naturally uncoupled. dbl-1 is expressed primarily in neurons and the DBL-1 ligand signals to its receptors and Smad signal transducers in the target tissue of the epidermis. The requirements constraining the source(s) of DBL-1, however, have not previously been investigated. We show here that dbl-1 expression requirements are strikingly relaxed. Expression in non-overlapping subsets of the endogenous expression pattern, as well as ectopic expression, can provide sufficient levels of activity for rescue of the small body size of dbl-1 mutants. By analysing dbl-1 expression levels in transgenic strains with different degrees of rescue, we corroborate the model that DBL-1 is a dose-dependent regulator of growth. We conclude that, for body size regulation, the site of expression of dbl-1 is less important than the level of expression.
The touch receptor neurons of the nematode Caenorhabditis elegans contain unusual 15-protofilament microtubules that are required for sensory transduction; other neurons in the nematode have ...11-protofilament microtubules. mec-7 is a gene that is necessary for the production of these microtubules; mec-7 mutants are touch insensitive, and their touch cells lack 15-protofilament microtubules but contain some 11-protofilament microtubules. I have shown that mec-7 encodes a $\beta$-tubulin, suggesting that constituent tubulins can affect microtubule structure. Genetic analysis of mec-7 shows that the absence of mec-7 function results selectively in the recessive loss of touch sensitivity. Partial loss-of-function alleles result in a partial loss of touch sensitivity. Many mec-7 mutations have dominant affects on touch sensitivity and probably encode abnormal tubulin products that interfere with microtubule assembly. I have sequenced the mutations in 45 mec-7 alleles and correlated these alterations with mutant phenotypes and expression patterns. Most of the dominant alleles contain mutations in one of three discrete regions of tubulin that may play a role in assembly; one other disrupts a putative GTPase domain. Most complete loss-of-function alleles are caused by nonsense mutations, insertions or deletions; three others disrupt a putative GTP-binding domain. The four complete loss-of-function alleles caused by missense mutations encode tubulins that may be defective in autoregulation. Finally, we would like to determine which amino acid residues are required for the production of 15-protofilament microtubules. To begin this study, I have mutated several mec-7 residues in vitro and tested their function by transformation of nematodes.
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