Journal Article

Stage specific requirement of platelet-derived growth factor receptor-α in embryonic development

Qian, Chen, Wong, Kenneth Kak Yuen, Wong, Carol Wing Yan, Wu, Zhongluan, He, Qiuming, Xia, Huimin, Tam, Paul Kwong Hang, Lui, Vincent Chi Hang

2017

Overview

Platelet-derived growth factor receptor alpha (PDGFRα) is a cell-surface receptor tyrosine kinase for platelet-derived growth factors. Correct timing and level of Pdgfra expression is crucial for embryo development, and deletion of Pdgfra caused developmental defects of multiple endoderm and mesoderm derived structures, resulting in a complex phenotypes including orofacial cleft, spina bifida, rib deformities, and omphalocele in mice. However, it is not clear if deletion of Pdgfra at different embryonic stages differentially affects these structures. To address the temporal requirement of Pdgfra in embryonic development. We have deleted the Pdgfra in Pdgfra-expressing tissues at different embryonic stages in mice, examined and quantified the developmental anomalies. Current study showed that (i) conditional deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele, and (ii) the day of Pdgfra deletion influenced the combinations, incidence and severities of these anomalies. Deletion of Pdgfra caused apoptosis of Pdgfra-expressing tissues, and developmental defects of their derivatives. Orofacial cleft, spina bifida and omphalocele are among the commonest skeletal and abdominal wall defects of newborns, but their genetic etiologies are largely unknown. The remarkable resemblance of our conditional Pdgfra knockout embryos to theses human congenital anomalies, suggesting that dysregulated PDGFRA expression could cause these anomalies in human. Future work should aim at defining (a) the regulatory elements for the expression of the human PDGFRA during embryonic development, and (b) if mutations / sequence variations of these regulatory elements cause these anomalies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abdominal wall / Abdominal Wall - abnormalities / Abdominal Wall - embryology / Abnormalities, Multiple - embryology / Abnormalities, Multiple - genetics / Abnormalities, Multiple - metabolism / Animal tissues / Animals / Anomalies / Apoptosis / Apoptosis - physiology / Biology and Life Sciences / Cell adhesion & migration / Cell surface / Cleft Lip - embryology / Cleft Lip - genetics / Cleft Lip - metabolism / Cleft Palate - embryology / Cleft Palate - genetics / Cleft Palate - metabolism / Clonal deletion / Congenital anomalies / Congenital defects / Defects / Deformation mechanisms / Deletion / Embryogenesis / Embryonic Development - physiology / Embryonic growth stage / Embryos / Endoderm / Etiology / Gene expression / Gene Expression Regulation, Developmental / Gene Knockout Techniques / Growth factors / Hernia, Umbilical - embryology / Hernia, Umbilical - genetics / Hernia, Umbilical - metabolism / Immunohistochemistry / In Situ Nick-End Labeling / Kinases / Medicine / Medicine and Health Sciences / Mesoderm / Mice / Mice, Inbred C57BL / Mice, Transgenic / Morphogenesis / Mutation / Neonates / Pediatrics / Platelet-derived growth factor / Protein-tyrosine kinase receptors / Proteins / Receptor, Platelet-Derived Growth Factor alpha - genetics / Receptor, Platelet-Derived Growth Factor alpha - metabolism / Regulatory sequences / Research and Analysis Methods / Rodents / Skeleton - abnormalities / Skeleton - embryology / Skeleton - metabolism / Smooth muscle / Spina bifida / Spinal Dysraphism - embryology / Spinal Dysraphism - genetics / Spinal Dysraphism - metabolism / Surgery / Tamoxifen / Time Factors / Tyrosine / Vertebra / Vertebrae