Prickle1mutation causes planar cell polarity and directional cell migration defects associated with cardiac outflow tract anomalies and other structural birth defects
| Autor: | Bishwanath Chatterjee, Brian C. Gibbs, Eszter K. Vladar, Cheng Cui, Hisato Yagi, Cecilia W. Lo, Heather L. Szabo-Rogers, Xiaoqin Liu, Yong Wan, Jeffrey D. Axelrod, Kaye Suyama, Maliha Zahid, George C. Gabriel, Rama Rao Damerla |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science Cell Mutant Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Ciliogenesis Cell polarity medicine Outflow tract Biology (General) Genetics Wnt signaling pathway Cell migration Actin cytoskeleton Cell biology 030104 developmental biology medicine.anatomical_structure Prickle1 Motile cilium Biliary atresia General Agricultural and Biological Sciences 030217 neurology & neurosurgery Research Article |
| Zdroj: | Biology Open, Vol 5, Iss 3, Pp 323-335 (2016) Biology Open |
| ISSN: | 2046-6390 |
| Popis: | Planar cell polarity (PCP) is controlled by a conserved pathway that regulates directional cell behavior. Here, we show that mutant mice harboring a newly described mutation termed Beetlejuice (Bj) in Prickle1 (Pk1), a PCP component, exhibit developmental phenotypes involving cell polarity defects, including skeletal, cochlear and congenital cardiac anomalies. Bj mutants die neonatally with cardiac outflow tract (OFT) malalignment. This is associated with OFT shortening due to loss of polarized cell orientation and failure of second heart field cell intercalation mediating OFT lengthening. OFT myocardialization was disrupted with cardiomyocytes failing to align with the direction of cell invasion into the outflow cushions. The expression of genes mediating Wnt signaling was altered. Also noted were shortened but widened bile ducts and disruption in canonical Wnt signaling. Using an in vitro wound closure assay, we showed Bj mutant fibroblasts cannot establish polarized cell morphology or engage in directional cell migration, and their actin cytoskeleton failed to align with the direction of wound closure. Unexpectedly, Pk1 mutants exhibited primary and motile cilia defects. Given Bj mutant phenotypes are reminiscent of ciliopathies, these findings suggest Pk1 may also regulate ciliogenesis. Together these findings show Pk1 plays an essential role in regulating cell polarity and directional cell migration during development. Summary: Outflow tract malalignment and multiple birth defects observed in the Prickle1 mutant may arise from cell polarity perturbation, which may involve disruptions in Wnt signaling and of cilia function. |
| Databáze: | OpenAIRE |
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