Inactivation of Cdc42 in neural crest cells causes craniofacial and cardiovascular morphogenesis defects.
Neural crest cells (NCCs) are physically responsible for craniofacial skeleton formation, pharyngeal arch artery remodeling and cardiac outflow tract septation during vertebrate development. Cdc42 (cell division cycle 42) is a Rho family small GTP-binding protein that works as a molecular switch to regulate cytoskeleton remodeling and the establishment of cell polarity. To investigate the role of Cdc42 in NCCs during embryonic development, we deleted Cdc42 in NCCs by crossing Cdc42 flox mice with Wnt1-cre mice. We found that the inactivation of Cdc42 in NCCs caused embryonic lethality with craniofacial deformities and cardiovascular developmental defects. Specifically, Cdc42 NCC knockout embryos showed fully penetrant cleft lips and short snouts. Alcian Blue and Alizarin Red staining of the cranium exhibited an unfused nasal capsule and palatine in the mutant embryos. India ink intracardiac injection analysis displayed a spectrum of cardiovascular developmental defects, including persistent truncus arteriosus, hypomorphic pulmonary arteries, interrupted aortic arches, and right-sided aortic arches. To explore the underlying mechanisms of Cdc42 in the formation of the great blood vessels, we generated Wnt1Cre-Cdc42-Rosa26 reporter mice. By beta-galactosidase staining, a subpopulation of Cdc42-null NCCs was observed halting in their migration midway from the pharyngeal arches to the conotruncal cushions. Phalloidin staining revealed dispersed, shorter and disoriented stress fibers in Cdc42-null NCCs. Finally, we demonstrated that the inactivation of Cdc42 in NCCs impaired bone morphogenetic protein 2 (BMP2)-induced NCC cytoskeleton remodeling and migration. In summary, our results demonstrate that Cdc42 plays an essential role in NCC migration, and inactivation of Cdc42 in NCCs impairs craniofacial and cardiovascular development in mice.
Department of Medical Physiology, College of Medicine, Texas A & M University Health Science Center, Temple, TX 76504, USA.
Yang
Y
Liu
Yixin
Y
Jin
Jieli
J
Li
Edward
E
Seto
Enoch
E
Kuo
Wei
W
Yu
Robert J
RJ
Schwartz
Maria
M
Blazo
Shenyuan L
SL
Zhang
Xu
X
Peng
D000199:Actins / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D018376:Cardiovascular Abnormalities / Q000196:embryology* / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D019465:Craniofacial Abnormalities / Q000196:embryology* / Q000201:enzymology* / Q000473:pathology; D003433:Crosses, Genetic; D003599:Cytoskeleton / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects; D009432:Neural Crest / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D055396:Bone Morphogenetic Protein 2; C581598:Cdc42 protein, mouse; D020764:cdc42 GTP-Binding Protein
Cdc42; Craniofacial malformation; GTPase; Migration; Neural crest cell; Persistent truncus arteriosus