How is vertebrate morphology encoded in the genome, and how does vertebrate morphology evolve? Vertebrate limbs are ideal structures in which to study these questions because they are both highly patterned and show remarkable changes in size and form in animals adapted to running, swimming, hopping, digging, or flying. Although many of the genes that control limb growth and patterning have been identified, we know relatively little about how the expression of these genes is regulated and to what degree changes in the regulation of these limb genes has contributed to the evolution of divergent limb morphologies. My lab uses a combination of comparative genomics and functional assays in knockout and transgenic mice to identify key cis-regulatory elements that control the expression of developmentally important limb genes. Current work is focused on the Tbx4 gene, which encodes a T-box transcription factor critical for the formation of the hindlimb. We have demonstrated that hindlimb expression of Tbx4 is controlled by at least two distinct enhancer elements, deletion of one of which reduces expression of Tbx4 in the hindlimb during embryogenesis and produces mice with characteristic decreases in the sizes of bones in the hindlimb. Comparative sequencing of vertebrate species that have evolved partial or complete hindlimb reduction indicates that reduction in the hindlimb size of some species has been accompanied by sequence changes in key hindlimb control regions of Tbx4. Future work will include the use of mouse transgenics and knock-in strategies to test the functional significance of Tbx4 hindlimb control elements during normal mouse development and the biological effects of sequence changes seen in other species.
Developmental regulation of gene expression; evolution of vertebrate limb morphology
Menke, D.B., C. Guenther and D.M. Kingsley. 2008. Dual hindlimb control elements in the Tbx4 gene and region-specific control of bone size in vertebrate limbs. Development(in press).
Baltus, A.E., D.B. Menke, Y.C. Hu, M.L. Goodheart, A.E. Carpenter, D.G. de Rooij and D.C. Page. 2006. In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nature Genetics 38: 1430-1434.
Koubova, J., D.B. Menke, Q. Zhou, B. Capel, M.D. Griswold and D.C. Page. 2006. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proceedings of the National Academy of Sciences, USA 103: 2474-2479.
Yao, H.H., M.M. Matzuk, C.J. Jorgez, D.B. Menke, D.C. Page, A. Swain and B. Capel. 2004. Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis.Developmental Dynamics 230: 210-215.
Natoli, T.A., J.A. Alberta, A. Bortvin, M.E. Taglienti, D.B. Menke, J. Loring, R. Jaenisch, D.C. Page, D.E. Housman and J.A. Kreidberg. 2004. Wt1 functions in the development of germ cells in addition to somatic cell lineages of the testis. Developmental Biology 268: 429-440.
Menke, D.B., J. Koubova and D.C. Page. 2003. Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. Developmental Biology 262: 303-312.
Menke, D.B. and D.C. Page. 2002. Sexually dimorphic gene expression in the developing mouse gonad. Gene Expression Patterns 2: 359-367.
Menke, D.B., G.L. Mutter and D.C. Page. 1997. Expression of DAZ, an azoospermia factor candidate, in human spermatogonia. American Journal of Human Genetics 60: 237-241.