As neural tube defects are amongst the most common birth defects, it is vitally important to understand the molecular mechanisms underlying neural tube development. Wnt signaling pathways have well-documented roles in neural tube closure and patterning/expansion of the dorsal spinal cord; however, little is known about how upstream regulators of Wnts affect neural tube development. Porcupine (Porcn) is an important upstream regulator of Wnt ligands and has been linked to neural tube defects in patients with Focal Dermal Hypoplasia. Porcn has a demonstrated role in the lipid modification of Wnt ligands, a post-translational modification that affects their activity and distribution. The objectve of the proposed work is to define the developmental role of Porcn in two distinct stages of neural tube development while assaying the specific roles of Porcn in downstream Wnt signaling pathways, using the chick neural tube as an in vivo model system. To attain the objective of this proposal, we plan to test our central hypothesis that Porcn regulates the closure of the neural tube and for the expansion and patterning of the dorsal spinal cord via b-catenin-dependent Wnt signaling. PUBLIC HEALTH RELEVANCE: As neural tube defects are amongst the most common birth defects, it is vitally important to understand the molecular mechanisms underlying neural tube development. The objective of the proposed work is to define the developmental role of Porcn, an upstream regulator of Wnt signaling, in two distinct stages of chick neural tube development while assaying the specific roles of Porcn in downstream Wnt signaling pathways. These experiments are expected to yield significant insights about the physiological roles of Wnt lipidation in neural tube development and to provide novel insights about a regulatory mechanism for Wnt ligands, which play key roles in the development of the CNS.