Steffen Biechele

Roles of the X-chromosomal Porcupine Gene in Wnt Signaling, Mouse Embryonic Development and Human Disease

Wnt signaling has been shown to play important roles in development and disease. In mammals, 20 Wnt ligands activate several different pathways such as the canonical Wnt signaling pathway, which acts through beta-catenin, and the non-canonical planar cell polarity (PCP) pathway. The highly conserved X-chromosomal gene Porcupine (Porcn) encodes an ER localized, predicted membrane-bound O-acyl transferase that is required for posttranslational lipid modification, secretion and gradient formation of several, if not all Wnt ligands. Mutations in the human homolog of Porcn have recently been associated with Focal Dermal Hypoplasia (FDH), an X-linked dominant disorder that is usually observed in females, with only rare cases of post-zygotic mutations in males. This suggests that a Porcn mutation could underlie some human cases of X-linked male lethality.

A mouse model that allows deletion of Porcn using the Cre-loxP technology has been generated and is used to address the early embryonic phenotype of Porcn mutant embryos. Tissue culture studies using mutant ES cells are used to elucidate the role of Porcn on a biochemical level and complement the in vivo studies.