The molecular underpinnings of human physiology and pathology can be sought out by the researcher, via biochemistry or forward genetics, or they can present themselves in the form of a patient seeking treatment for a common or rare congenital disorder. These dual approaches frequently converge, as in the case of the X-linked dominant human disorder focal dermal hypoplasia (FDH). This syndrome was recently mapped to the PORCN gene, the unique homolog of a Drosophila gene, porcupine, required for secretion of Wnt ligands. Although Wnts are thought to regulate many aspects of development and disease, genetic studies of ligand function in mammals are complicated by redundancy among the 19 family members. To establish a genetic tool with which to overcome this redundancy, our lab generated a conditional knockout allele of mouse Porcn and demonstrated that it provides an animal model of FDH. Building on our recently published findings, we propose here to examine two novel and disease-relevant phenotypes associated with FDH, ectopic fat deposition and incomplete body wall closure, to which our mouse model provides unique access. Our preliminary findings indicate that these phenotypes share an ectodermal etiology, which we will investigate in three specific aims: (1) determine the requirement for Porcn in production of ectodermally-expressed Wnt proteins;(2) characterize the role of Porcn-mediated Wnt signals in suppressing adipogenesis;(3) analyze Porcn mutant mice as a model for body wall closure defects. These studies will firmly establish the utility of Porcn mutants as an FDH model and as a tool to inhibit Wnt signaling in vivo. They will also provide new insight into understudied aspects of developmental biology, with connections to human disease, and establish a new Porcn/Wnt-focused research program in our lab.
Focal dermal hypoplasia (FDH) is a rare disease that affects the Wnt signaling pathway, which itself is very commonly dysregulated in additional congenital and acquired diseases. FDH is caused by mutations in the PORCN gene, for which we have generated a novel mouse genetic model. This proposal focuses on aspects of FDH that are also relevant to other diseases, and highlights the usefulness of mouse PORCN mutants to model disorders of Wnt signaling in humans.