genetic and cell biological analyses of development in the mouse
	Frank Ruddle, Ph.D. Professor Emeritus Email: frank.ruddle@yale.edu Room: KBT 1010A Phone: (203) 432-3520 Fax: (203) 432-5690

Our principal research interest is development/evolution, and the relationship between the two. In the developmental area, we have been concerned with mechanisms that define morphogenetic identities over the anterior/posterior axis of multicellular organisms. With respect to evolution, we are interested in how different body plans are determined by a modification of morphogenetic identities. The mouse serves as our principal experimental system, and we use developmentally relevant genes, such as homeobox and hox cluster genes, as entry points to study mechanisms that determine growth and form. There are 38 Hox genes in the mouse and these are arranged in four clusters of approximately 100 kb length that map to different chromosomes. Sequence and architectural studies of these clusters in a broad array of metazoans strongly indicate that the gene family has increased by (1) lateral gene duplication to give rise to a single gene cluster, and (2) a multiplication of clusters to the four cluster level. The increase in Hox gene number is associated with increased morphological complexity. We have selected several genes from this family for intensive analysis. We have concerned ourselves particularly with understanding transcriptional regulation and cis control within the gene cluster. Our primary experimental methods are those of molecular biology, developmental genetics, and transgenic modification of embryos. Currently, we have identified a number of Hox gene enhancers and their subelements. A major effort is being made to understand how these elements function in terms of protein/DNA binding, protein/protein interaction, and chromatin structure. We are also attempting to identify enhancer orthologs in other mammals, birds, bony fishes, elasmo-branches, and cyclostomes. The introduction of enhancer elements from foreign species of different phylogenetic relatedness into mice as reporters and "knock-ins" serves as a means to deter-mine their functional similarities.

Selected Publications

Bradshaw, M. S., C. S. Shashikant, H.-G. Belting, J. A. Bollekens and F. H. Ruddle (1996). A long range regulatory element of Hoxc-8 identified using the pClasper vector. Proc. Natl. Acad. Sci. USA 93:2426-2430.

Shashikant, C. S. and F. H. Ruddle (1996). Combinations of closely situated cis-acting elements determine tissue-specific patterns and anterior extent of early Hoxc8 expression. Proc. Natl. Acad. Sci. USA 93:12364-12369.

Shashikant, C.S., J.L. Carr, J.Bhargava, K.L. Bentley and F.H. Ruddle (1998). Recombinogenic targeting: a new approach to genomic analysis -- a review. Gene 223:9-20

Shashikant, C.S., C.B. Kim, M.A. Borbely, W.C.H. Wang and F.H. Ruddle (1998). Comparative studies on mammalian Hoxc8 early enhancer sequence reveal a baleen whale-specific deletion of a cis-acting element. Proc. Natl. Acad. Sci. USA 95:15446-15451

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