Cell surface regulation of Hedgehog signaling during mouse embryogenesis. During embryogenesis many developmental decisions are regulated by a relatively small number of secreted growth factors and morphogens. These secreted ligands elicit a multitude of cellular responses, often functioning as morphogens, mitogens, survival factors and chemoattractants within the same tissue. Our research is focused on understanding how these signaling pathways elicit such a diverse set of responses within the developing embryo and how their selective modulation might contribute to the treatment of both developmental diseases and cancer. Specifically, we seek to understand the regulation of Hedgehog (Hh) signaling in development and disease through the study of this pathway during mouse embryogenesis. Hh signaling proteins govern multiple developmental processes ranging from the establishment of left-right asymmetry to neural patterning and digit specification. Hh ligands also regulate a number of adult homeostatic processes including the maintenance of neural stem cell niches. In humans, impaired Hh signaling leads to severe birth defects, such as holoprosencephaly, while improper Hh pathway activation is associated with a number of cancers, including medulloblastoma, basal cell carcinoma and rhabdomyosarcoma. A defining feature of Hh signaling is that relatively small changes in the concentration of Hh ligand elicit dramatically different cellular responses. This is most evident in the developing neural tube, where Sonic Hedgehog (Shh) signaling is required for the specification of all ventral cell fates. During neural patterning, as little as a two-fold change in Shh ligand concentration is sufficient to specify distinct cell types. This raises the question: How do cells sense subtle differences in ligand concentration? Recent work suggests that feedback mechanisms acting at the level of ligand binding play a critical role in determining the proper cellular response. We study the function of several Hh-binding proteins (Ptch1, Ptch2, and Hhip1) that antagonize Hh function, as well as the characterization of three novel Hh-binding cell surface proteins, Gas1, Cdo and Boc that promote Hh signaling. We are also pursuing the identification and characterization of additional cell surface proteins that may regulate Hh signaling during embryogenesis. We seek to explore the functions of these molecules using a wide range of approaches, including mouse developmental genetics, biochemistry, and cell biology.