Phenotypic and functional characterization of craniofacial bone development in Ellis-Van Creveld Syndrome 2 (EVC2) knockout mouse
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Ellis-van Creveld syndrome (EvC) is a rare chondro-ectodermal dysplasia with an autosomal recessive trait affecting bone and cartilage growth. EvC patients have mutations in either the EVC or EVC2 gene, both of which are located on chromosome 4 in a head-to-head configuration. The clinical manifestations of the disease-phenotype could be highlighted in four major congenital anomalies: chondral dysplasia, manifested as a disproportionate dwarfism; ectodermal dysplasia of the nails, teeth, and sometimes hair; polydactyly (postaxial sixth finger); and congenital heart disease in up to 60% of cases. ln addition, several reports indicated phenotypic involvement of the craniofacial structures. There were several cases reported that an abnormal craniofacial bone phenotype was observed in Ellis-Van Creveld syndrome (EvC) patients; however, it is currently unknown whether mutation of EVC or EVC2 genes causes such craniofacial bone phenotypes. Our objective is to investigate and characterize the craniofacial phenotype using Evc2 knockout (KO) mice, Evc2 KO mice were used in this study as an animal model of EvC syndrome, and craniofacial bone development/phenotype in these mice was investigated in comparison to wild type mice. Lateral cephalometric radiographs were acquired and cephalometric analysis was performed on three postnatal age groups [one (n=15), three (n=15), and six (n=13) weeks old]. The expression pattern of Evc2 was investigated in the craniofacial tissues and proliferation and apoptosis in endochondral ossification bones and growth plates were examined in the developing embryos at E15.5-E18.5 and postnatal samples at 3 weeks. Skeletal double staining of WT and KO postnatal samples with alcian blue and alizarin red and histological examination were investigated. Our data showed that the postnatal bone growth deficiency in KO mice was found in the areas where expression of Evc2 was observed. Growth rate of craniofacial bones in KO mice was reduced to 72-79% of that of controls at the time points tested. Notably, growth of certain bones including nasal bone, palatal bone and premaxilla was more affected in KO than that in the controls. Furthermore, there was a remarkable change in facial bones' spatial relationship to the cranial base and vault. We also found an enhanced apoptosis and abnormal profile ration pattern in KO compared to WT. We concluded that Evc2 is essential for craniofacial bone development and deficiency in Evc2 leads to specific facial bone growth defects due to imbalances of cellular profile ration and abnormal levels of cell death.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact email@example.com.Dissertation (DScD) --Boston University, Henry M. Goldman School of Dental Medicine, 2014 (Department of Molecular and Cell Biology).Includes bibliography: leaves 107-116.
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