부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2017.02.021 Byline: Grethel Millington (a)(b), Kelsey H. Elliott (a)(b), Ya-Ting Chang (a)(b), Ching-Fang Chang (a)(b), Andrzej Dlugosz (c), Samantha A. Brugmann (a)(b) Abstract: Ciliopathies are a class of diseases caused by the loss of a ubiquitous, microtubule-based organelle called a primary cilium. Ciliopathies commonly result in defective development of the craniofacial complex, causing midfacial defects, craniosynostosis, micrognathia and aglossia. Herein, we explored how the conditional loss of primary cilia on neural crest cells (Kif3a.sup.f/f ;Wnt1-Cre) generated aglossia. On a cellular level, our data revealed that aglossia in Kif3a.sup.f/f ;Wnt1-Cre embryos was due to a loss of mesoderm-derived muscle precursors migrating into and surviving in the tongue anlage. To determine the molecular basis for this phenotype, we performed RNA-seq, in situ hybridization, qPCR and Western blot analyses. We found that transduction of the Sonic hedgehog (Shh) pathway, rather than other pathways previously implicated in tongue development, was aberrant in Kif3a.sup.f/f ;Wnt1-Cre embryos. Despite increased production of full-length GLI2 and GLI3 isoforms, previously identified GLI targets important for mandibular and glossal development (Foxf1, Foxf2, Foxd1 and Foxd2) were transcriptionally downregulated in Kif3a.sup.f/f ;Wnt1-Cre embryos. Genetic removal of GLI activator (GLIA) isoforms in neural crest cells recapitulated the aglossia phenotype and downregulated Fox gene expression. Genetic addition of GLIA isoforms in neural crest cells partially rescued the aglossia phenotype and Fox gene expression in Kif3a.sup.f/f ;Wnt1-Cre embryos. Together, our data suggested that glossal development requires primary cilia-dependent GLIA activity in neural crest cells. Furthermore, these data, in conjunction with our previous work, suggested prominence specific roles for GLI isoforms; with development of the frontonasal prominence relying heavily on the repressor isoform and the development of the mandibular prominence/tongue relying heavily on the activator isoform. Author Affiliation: (a) Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States (b) Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States (c) Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States Article History: Received 30 December 2016; Revised 20 February 2017; Accepted 20 February 2017