The Role of Astrotactin2 in Regulating Mammalian Skin Polarity

The study identified the exon 5 deletion in Astrotactin2 (Astn2) as a genetic modifier affecting hair follicle orientation in mammalian skin, contributing to planar cell polarity (PCP) signaling. Researchers defined Astn2 as a two transmembrane protein with extracellular N- and C-termini and discovered it undergoes intramembrane proteolytic cleavage in the second transmembrane segment (TM2). This cleavage was unaffected by replacing TM2 with the transmembrane domain of CD74 or 21 alanines but was eliminated by substituting TM2 with domains from CD4, the Asialoglycoprotein receptor, or the Transferrin receptor, or by leucine substitution near the cleavage site. These findings highlighted intramembrane proteolysis as crucial for Astn2 maturation and its role in skin PCP.