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标题：Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice
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作者：Ricardo Villares ; Julio Gutiérrez ; Agnes Fütterer 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：4803-4808
DOI：10.1073/pnas.1419300112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe primary cilium is an organelle protruding from most postmitotic vertebrate cells. A growing body of data supports the crucial role of primary cilia in developmental signaling pathways. Recent studies describe the main stages in ciliogenesis at the morphological level and components of some of the mechanisms involved, including the selective acetylation of tubulin. How this acetylation is modulated in cilia nonetheless remains poorly understood. Here we show that the death inducer-obliterator (dido) gene product, which regulates histone deacetylase 6 deacetylase activity, is necessary for orofacial development in the mouse embryo and influences brain patterning and neuromuscular activity. Mice deficient in dido function present neonatal mortality and various ciliopathies including cleft palate and hydrocephalus, as well as hippocampal and commissural dysplasia. Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sanchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia.
关键词：ciliopathies ; brain patterning ; perinatal lethality