Genetic mutations which transform cells from one developmental fate into another provide a means of tackling this problem as they are likely to be affecting genes involved in the choice of a particular fate. One C. elegans mutant, mab-9 (male abnormal), has gross defects in tail development because of a transformation in the identity of two particular cells which are normally very important for correct tail development. In mab-9 mutants these two cells take on an inappropriate fate, and so the development of the tail goes wrong. mab-9 is therefore a key regulatory gene which dictates the distinguishing characteristics of individual cells. Understanding how genes of this type operate in molecular terms is one of the central goals of research in developmental biology.
I have recently cloned the mab-9 gene and discovered that it encodes a member of the T-Box family of transcription factors, the prototype of which, Brachyury, was first identified as a mutation disrupting tail development in mouse. We are beginning to discover important clues as to how this transcription factor may be acting on a molecular level to dictate the developmental fates of particular cells. We are also interested in other C. elegans T-box genes. For example, we have recently defined a genetic network important for posterior patterning involving tbx-8, tbx-9 and tbx-30 as well as mab-9.
Another important project in the lab concerns the regulation of cell number during development. How is cell proliferation controlled so that the correct numbers of cells are produced in the right place at the required time? One mutant we have been working on, mab-2, has defects in male tail development because crucial cell divisions fail. We have discovered that mab-2 encodes a Runt family transcription factor essential for cell proliferation during C. elegans development. Interestingly, when worms express too much mab-2, extra cell divisions take place. The human orthologues of this gene are all implicated in human cancers, suggesting an intriguing link between the role of Runt transcription factors in regulating C. elegans cell proliferation, and human carcinogenesis. The worm promises to be an excellent model system for the further analysis of this link, and for the isolation of other factors required to regulate cell division during development.