Autonomous and non-cell autonomous role of cilia in structural birth defects in mice

by Richard J. B. Francis, Jovenal T. San Agustin, Heather L. Szabo Rogers, Cheng Cui, Julie A. Jonassen, Thibaut Eguether, John A. Follit, Cecilia W. Lo, Gregory J. Pazour Ciliopathies are associated with wide spectrum of structural birth defects (SBDs), indicating important roles for cilia in development. Here, we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency inIft140, an intraflagellar transport (IFT) protein regulating ciliogenesis.Ift140-deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula (TEF), randomized heart looping, congenital heart defects (CHDs), lung hypoplasia, renal anomalies, and polydactyly. Tamoxifen inducibleCAGGCre-ER deletion of a floxedIft140 allele between E5.5 to 9.5 revealed early requirement forIft140 in left-right heart looping regulation, mid to late requirement for cardiac outflow septation and alignment, and late requirement for craniofacial development and body wall closure. Surprisingly, CHD were not observed with 4 Cre drivers targeting different lineages essential for heart development, but craniofacial defects and omphalocele were observed withWnt1-Cre targeting neural crest andTbx18-Cre targeting epicardial lineage and rostral sclerotome through which trunk neural crest cells migrate. These findings revealed cell autonomous role of cilia in cranial/trunk neural c...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research