Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate
| Autor: | William P. Magee, Yuan Yuan, Hua Tian, Jifan Feng, Pedro A. Sanchez-Lara, Jane C. Figueiredo, Jingyuan Li, Frederick Brindopke, Thach-Vu Ho, Yang Chai, Yang Liu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Mesenchyme Cleft Lip Embryonic Development Wnt1 Protein Biology Ciliopathies Mesoderm 03 medical and health sciences Mice Cranial neural crest Intraflagellar transport Genetics medicine Animals Humans Craniofacial Molecular Biology Genetics (clinical) Cell Proliferation Palate Cilium Tumor Suppressor Proteins Neural crest Gene Expression Regulation Developmental General Medicine Anatomy Articles Cell biology 030104 developmental biology medicine.anatomical_structure Bilateral cleft lip Neural Crest Signal Transduction |
| Zdroj: | Human molecular genetics. 26(5) |
| ISSN: | 1460-2083 |
| Popis: | Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G>C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting. In order to evaluate the function of IFT88 in regulating craniofacial development, we generated Wnt1-Cre;Ift88(fl/fl) mice to eliminate Ift88 specifically in cranial neural crest (CNC) cells. Wnt1-Cre;Ift88(fl/fl) pups died at birth due to severe craniofacial defects including bilateral cleft lip and palate and tongue agenesis, following the loss of the primary cilia in the CNC-derived palatal mesenchyme. Loss of Ift88 also resulted in a decrease in neural crest cell proliferation during early stages of palatogenesis as well as a downregulation of the Shh signaling pathway in the palatal mesenchyme. Importantly, Osr2KI-Cre;Ift88(fl/fl) mice, in which Ift88 is lost specifically in the palatal mesenchyme, exhibit isolated cleft palate. Taken together, our results demonstrate that IFT88 has a highly conserved function within the primary cilia of the CNC-derived mesenchyme in the lip and palate region in mice and is a strong candidate as an orofacial clefting gene in humans. |
| Databáze: | OpenAIRE |
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