S Steven Potter
Childrens Hospital Bldg R
COM Pediatrics Dev. Biology - 0054
My research group studies the molecular genetics of mammalian development. We are particularly interested in understanding the genetic programs that direct the formation of the limbs, kidneys, brain and heart.We study a family of genes that have been shown to be master switch genetic regulators in simpler organisms. These genes are related by sharing a common 180 base pair sequence, the homeobox. A mutation in one of these fruit fly genes, Antennapedia, can cause the cells that normally make antennae instead to make legs that now protrude from the head. A mutation in another, Bithorax, can cause the transformation of an abdominal segment into a thoracic segment, complete with an extra set of wings. These genes are extremely well- conserved during evolution. My group studies the mammalian counterparts, working to understand their role in development.We study several of these genes, which are known to be transcription factors that control the expression patterns of batteries of downstream target genes. Some of the targets can include other transcription factor genes. These genes can thereby initiate genetic cascades that result in wholesale changes in genes expression patterns and control the developmental destinies of groups of cells.The Hoxa 11 gene was originally cloned by our group. We have shown that it is expressed during in the developing limbs, kidneys and reproductive tracts of males and females. We directly addressed the question of function by generating mice with a targeted mutation in Hoxa 11. Both skeletal defects, including malformations of limb bones, and reproductive defects were observed. In a collaborative effort with the Mario Capecchi group we also generated mice with both of the similar Hox genes, Hoxa 11 and Hoxd 11, targeted. The resulting mice were very striking, with large regions of limb structures deleted. This work shows that these genes have overlapping function. When one gene is absent, the other can largely compensate, but when both are gone we found profound defects. In the single mutants, for example, the kidneys were normal, but in the double mutants, the kidneys were absent or extremely small.For Hoxa 11 we have also found the presence of abundant antisense transcripts that show an intriguing expression pattern in the developing limb that is complementary to that of the sense transcripts. When the antisense transcripts appear, the sense transcripts disappear from that region, suggesting that these antisense RNAs may play a natural endogenous regulatory role in regulating the stability of sense RNAs.In addition to Hoxa 11 the lab studies Gsh-1, Gsh-2, Gsh-4, S-8, Pmx and other homeobox genes using the same strategy of structure, expression and mutational analysis. Much of our future focus is on the identification of upstream regulators and downstream genetic targets, so that we can better decipher the genetic programs of development.
Development,Gene Targeting,Homeobox Genes,Molecular Genetics