REGENTS OF THE UNIVERSITY OF MINNESOTA
We study the molecular mechanisms controlling gradient formation by morphogens, signaling molecules that specify different cell fates at distinct concentration and signaling thresholds. These molecules provide a fundamental mechanism of generating patterns during tissue assembly. In the fruitfly Drosophila, secreted factors such as Decapentaplegic (Dpp), Wingless (Wg), and Hedgehog have been shown to act as morphogens. In addition, it has been well established that glypicans, a family of heparan sulfate proteoglycans (HSPGs), control the activity and distribution of morphogens during development. We focus on the functions of two Drosophila glypicans, Dally and Dally-like, in controlling the distribution of Dpp and Wg in developing tissues. Our studies demonstrated that HSPGs regulate membrane trafficking and endocytosis of morphogens to shape their concentration gradients. To understand the molecular mechanism by which HSPGs affect morphogen gradients, we propose to study the effect of HSPGs on the subcellular localization of the internalized morphogens, and examine the genetic (functional) interactions between HSPG genes and endocytosis regulators. These experiments will provide novel insights into the regulatory mechanism for morphogen gradient formation.