title: Analysis of PRICKLE1 in human cleft palate and mouse development demonstrates rare and common variants involved in human malformations.
abstract: Palate development is shaped by multiple molecular signaling pathways, including the Wnt pathway. In mice and humans, mutations in both the canonical and noncanonical arms of the Wnt pathway manifest as cleft palate, one of the most common human birth defects. Like the palate, numerous studies also link different Wnt signaling perturbations to varying degrees of limb malformation; for example, shortened limbs form in mutations of Ror2,Vangl2 (looptail) and, in particular, Wnt5a. We recently showed the noncanonical Wnt/planar cell polarity (PCP) signaling molecule Prickle1 (Prickle like 1) also stunts limb growth in mice. We now expanded these studies to the palate and show that Prickle1 is also required for palate development, like Wnt5a and Ror2. Unlike in the limb, the Vangl2looptail mutation only aggravates palate defects caused by other mutations. We screened Filipino cleft palate patients and found PRICKLE1 variants, both common and rare, at an elevated frequency. Our results reveal that in mice and humans PRICKLE1 directs palate morphogenesis; our results also uncouple Prickle1 function from Vangl2 function. Together, these findings suggest mouse and human palate development is guided by PCP-Prickle1 signaling that is probably not downstream of Vangl2.
authors.affiliation: Department of Biology, University of Iowa Iowa City, Iowa, 52242.
authors.forename: Tian
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, University of Iowa Iowa City, Iowa, 52242 ; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University Chengdu, China ; Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University Chengdu, China.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Division of Biological Sciences, University of Missouri Columbia, Missouri, 65211.
authors.forename: Whitney
authors.initials: W
authors.lastname: Bryant-Pike
authors.affiliation: Division of Biological Sciences, University of Missouri Columbia, Missouri, 65211.
authors.forename: Anand
authors.initials: A
authors.lastname: Chandrasekhar
authors.affiliation: Department of Pediatrics, University of Iowa Iowa City, Iowa, 52242.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Department of Biology, University of Iowa Iowa City, Iowa, 52242.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
authors.affiliation: Department of Pediatrics, University of Iowa Iowa City, Iowa, 52242.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
keywords: Cleft palate; Prickle1; Shh; Vangl2