Massachusetts General Hospital

The goal of my lab is to understand the molecular genetics of appendage formation in vertebrates.

The focus of my research is on the process by which competent cells are allocated to distinct fates in appropriate numbers and positions to generate organized structures. We have developed the chick feather field as a system to study the molecular genetics of this process in vivo and in vitro. The relatively simple yet highly organized pattern of feather buds is an experimentally tractable system to study the interactions between intercellular signaling pathways that specify organizing centers and mediate their activity. We have divided the process of pattern formation in the feather field to a series of discrete steps with molecular markers to identify them. In this way, we can untangle the interactions between multiple signaling pathways in a single event and then reconstruct the sequential roles of each pathway in the ultimate generation of a feather tract. We have identified roles for Sonic hedgehog, BMPs, FGFs, Wnts and the Notch signaling pathway and are studying interactions between these pathways to generate pattern during tract morphogenesis.

To complement the analysis of gene function in intact tissues, we have developed methods to purify specific cell populations in the hair follicle using transgenic mice expressing fluorescent proteins under the control of cell type specific promoters. This allows us to take advantage of whole genome approaches to identify new signals involved in cell- cell interactions in the follicle and to dissect specific inductive interactions. This work has confirmed the similarity between follicle formation in mouse and chick embryos and follicle regeneration in the adult and we continue to move between these experimental systems to test the function of candidate genes.

Another aspect of the pattern formation process is the restriction of potential in muli-potent cells as development proceeds. A second focus of research in the lab is on the role of the Ikaros family of transcription factors on the specification of cell potential. We hope to discern the manner in which alterations in the nucleus of the cell contribute to the changing response to extrinsic signals which is an integral part of pattern formation. We have cloned three additional genes, which with Ikaros make up the Ikaros gene family. We use gain and loss of function experiments in mice, chicks and frogs to analyze their roles in specific lineages.