During embryonic development, key regulatory molecules specify the fates of individual cells as well as the overall shapes, sizes and distributions of organs and other structures. Mutations in such regulatory genes often result in serious congenital malformations. Our laboratory is interested in studying the molecular and cellular mechanisms by which such regulatory genes direct mammalian skin and limb development.

Working in collaboration with Dr. Alexandra Joyner, also at the NYU School of Medicine, we have shown that Engrailed-1 (En1), a homeodomain-containing transcription factor, is essential for dorsal-ventral patterning of the developing limb and overlying skin. Loss of En1 function results in the loss of ventral (palmar) limb structures, such as sweat glands and sesamoid bones, and the ventral duplication of dorsal paw structures, such as hairs and nails. Our studies have shown that En1 directs ventral limb development in part by inhibiting ventral ectoderm expression of "dorsalizing" signalling molecules, which can then reprogram the adjacent mesenchyme to a dorsal fate. Our more recent studies indicate that En1 also acts during later palmer/planter ectoderm differentiation as well as during interfollicular mesenchyme differentiation. We are interested in using these and other mouse mutants to further investigate the genetic regulation of skin and epidermal appendage (hair, gland and nail) development as it relates to dorsal-ventral patterning of the limb as well to other body sites, such as the head.

In addition to its early and late functions in dorsal-ventral limb patterning, we have also shown that En1 is required to promote maturation of the apical ectodermal ridge (AER), a signalling center required for distal limb outgrowth. In the absence of En1, the AER precursor cells are delayed in their initiation of the morphogenetic movements necessary to form a tightly compacted ridge along the distal limb margin. This initial delay in AER compaction frequently results in the formation of ectopic AERs and the subseqeunt development of ectopic digits. We are using a variety of genetic strategies, including the generation of double mutants as well as transgenic and chimeric mice, to investigate the underlying mechanisms governing AER formation.