Section: Research

Siu Ing The, Ph.D.

Academic Role: Adjunct Professor

Faculty Appointment(s) In:
   Program in Gene Function and Expression

Hedgehog Signaling and Distribution in Drosophila melanogaster

Cell-cell signaling plays a major role in shaping organisms during development. Following their production, extracellular factors are secreted and diffuse to reach their cognate receptors on the target cells. The signal transduction pathways downstream of the receptors have been studied extensively. However, we know very little about the mechanisms regulating transport, secretion and distribution of extracellular factors.

Secreted proteins need to find their way through a dense extracellular matrix of collagen, hyaluran, and proteoglycans. This transport is further complicated by the fact that some proteins, like members of the Hedgehog family, are tethered to the membrane via a cholesterol moiety. Despite this membrane "anchor" they can signal to cells several cell diameters away. Understanding how the Hedgehog ligand is transported to reach its target cells is an important biological question, as Hedgehog is a key developmental signal in the fruitfly Drosophila melanogaster as well as vertebrates. Moreover, abnormal Hedgehog signaling contributes to a variety of human cancers.

We use a combination of Drosophila genetics, molecular biology and immunohistochemistry to study the mechanisms of Hedgehog distribution and signaling. We have discovered a Drosophila gene, tout velu, that is essential for the proper distribution of the Hedgehog molecule. tout velu is a member of the EXT gene family, which is involved in a human syndrome called "multiple exostoses". This syndrome is characterized by bone extrusions and bone tumors. Surprisingly, the Tout velu and Ext proteins are glycosyltransferases involved in Heparan Sulfate Proteoglycan (HSPG) biosynthesis. Our research focuses on how HSPGs affect transport and/or localization of Hedgehog. In addition, we use genetic screens to identify other genes that affect Hedgehog distribution and signaling. As the components of the Hedgehog signaling cascade are similar in humans, our results are expected to apply broadly and contribute to our understanding of Hedgehog 's role in human development and carcinogenesis.

Office: 621
Phone: 508 856-5294
E-mail: SiuIng.The@umassmed.edu
Keywords: Genetic Systems, Signal Transduction, Developmental Biology

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