Worm Breeder's Gazette 14(2): 44 (February 1, 1996)
These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
Waksman Institute, Rutgers University, Piscataway, NJ 08855
The TGF-b superfamily comprises a group of secreted proteins which are involved in fundamental biological processes including, but not limited to, axis specification, mesoderm induction, osteogenic differentiation, tissue regeneration, and neoplastic growth. There is significant primary structure homology shared among all the members, and the superfamily can be further partitioned into groups based upon homology and function. These families include the dpp/BMP group, the activin/inhibin family, the TGF-b subset, the MIS family, and others. Though there has been intense interest in recent years to determine the pathways by which TGF-b signalling occurs, the mechanism by which the signal is transduced from a TGF-b superfamily members is still relatively poorly understood. Membrane receptors which specifically bind with TGF-b-like ligands have been identified and are being characterized in several organisms. A subset of these receptors contain a serine-threonine kinase domain, and can be categorized into two classes, type I and type II, which differ considerably with each other in their non-kinase regions. A general model for the transduction of the TGF-b-like signal involves an initial proteolytic modification of the ligand followed by binding of mature cysteine-bridged dimeric form with the type II receptor. Upon binding, interaction between the two types of receptors can occur, and mutual phosphorylation is implicated in receptor activation. In this activated state, the receptor kinases presumably are then capable of transducing the signal through the phosphorylation of other targets. This cascade would eventally result in biochemical changes and altered expression patterns of specific genes. In our laboratory, we have been trying to elucidate of the TGF-b signal transduction system in C. elegans. We have identified candidate genes at each step of the transduction process in the nematode using a variety of methods. Putative homologs at the metalloprotease (Finelli et al., this Gazette), ligand, and receptor (Krishna et al., this Gazette) level have been identified and are being characterized. Additionally, attempts to isolate downstream components have yielded the dwarfin family of potential downstream mediators (Das et al., this Gazette), including sma-2, sma-3, and sma-4, which have been implicated in the pathway through both molecular and genetic observations (Savage et al., this Gazette). In C. elegans, dbl-1 (formerly ceg-1; Yandell and Wood, WBG, 1994) and daf-7 (pers. comm. D. Riddle) have been the previously reported TGF-b superfamily member. Sequence alignment analysis had revealed that dbl-1 bears considerable homology to dpp, a developmentally significant molecule in Drosophila. DAF-7 is a divergent ligand which has been implicated in the dauer pathway. However, there were several lines of evidence that illuminated the possibility that other TGF-b-like ligands exist in the nematode. First, comparison with other organisms such as Drosophila, in which multiple superfamily members have been identified and characterized, suggests that an analogous situation may exist in the worm. Secondly, both DPP and BMP-4 have been shown to bind with DAF-4 in-vitro; thus we hypothesized that in the worm, multiple dpp/BMP-related ligands should be present. tig-1 and tig-2, acronyms for TGF-b-like ligand, were identified using a combination of PCR and database searches against the sequencing project. These genes are located on cosmids C53D6 and F39G3, respectively. Evolutionary trees constructed using with a variety of TGF-b superfamily members indicate that tig-1 and tig-2 show homology to the 60A and screw genes of Drosophila. We are currently trying to establish a definitive evolutionary relationship among the homologs. In addition, mutations in tig-1 and tig-2 are being sought which would indicate their role in devlopment and place them into known TGF-b-like signalling pathways.