UC San Diego

To understand the function of heparan sulfate in branching morphogenesis in the mammary gland, we have generated mice containing conditional mutations of heparan sulfate biosynthetic enzymes in mammary epithelial cells. Tissue specific alteration of heparan sulfate was accomplished by crossbreeding mice bearing loxP flanked alleles with transgenic mice that express the Cre recombinase specifically in mammary epithelia before ductal branching (MMTV Cre). In chapter 2 we show that altering the polymerization or overall sulfation of the chain inhibits mammary epithelial proliferation leading to failure of ductal branching. Inhibition of 2-O-sulfation of the chain did not inhibit proliferation but blocked dichotomous and side branching. In contrast, diminution of overall sulfation of the chain had no effect on branching, but blocked lobuloalveolar formation (chapter 4). In vitro studies show that the activity of multiple heparin binding growth factors was affected. Prior studies suggested an crucial role for hepatocyte growth factor (HGF) in mammary ductal development, but deletion of the Met receptor (through which HGF signals) did not effect mammary development (chapter 3). These studies demonstrate that heparan sulfate is a key regulator in mammary development and function. This thesis provides a springboard for examining individual growth factors in branching morphogenesis