| A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling. | |
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MedLine Citation:
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PMID: 19776033 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Meckel syndrome (MKS) is a rare autosomal recessive disease causing perinatal lethality associated with a complex syndrome that includes occipital meningoencephalocele, hepatic biliary ductal plate malformation, postaxial polydactyly and polycystic kidneys. The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes. However, shRNA knockdown studies in cell culture have reported conflicting results on the role of Mks1 in ciliogenesis. Here we show that loss of function of mouse Mks1 results in an accurate model of human MKS, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development and the kidney that mirror the human syndrome. In contrast to cell culture studies, loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues. Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects, although both tissues show an expansion of the domain of response to Shh signaling, unlike the phenotypes seen in other mutants with cilia loss. Other defects in the skull, lung, rib cage and long bones are likely to be the result of the disruption of Hh signaling, and the basis of defects in the liver and kidney require further analysis. Thus the disruption of Hh signaling can explain many, but not all, of the defects caused by loss of Mks1. |
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Authors:
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Scott D Weatherbee; Lee A Niswander; Kathryn V Anderson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-09-22 |
Journal Detail:
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Title: Human molecular genetics Volume: 18 ISSN: 1460-2083 ISO Abbreviation: Hum. Mol. Genet. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-05 Completed Date: 2010-02-12 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: England |
Other Details:
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Languages: eng Pagination: 4565-75 Citation Subset: IM |
Affiliation:
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Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA. scott.weatherbee@yale.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Abnormalities, Multiple
/
embryology,
genetics,
metabolism*,
physiopathology Animals Cilia / genetics, physiology* Disease Models, Animal* Female Gene Knockdown Techniques Hedgehog Proteins / genetics, metabolism* Humans Male Mice* Mice, Inbred C3H Mice, Inbred C57BL Proteins / genetics, metabolism* Signal Transduction* |
| Grant Support | |
ID/Acronym/Agency:
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R01 HD32427/HD/NICHD NIH HHS; R01 NS044385/NS/NINDS NIH HHS; U01 HD43478/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hedgehog Proteins; 0/MKS1 protein, mouse; 0/Proteins; 0/Shh protein, mouse |
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