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Elife ; 72018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30070635


We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a-/- embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a-/- embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at E9.5 in Fam60a-/- embryos, suggesting that DNA demethylation is enhanced in the mutant. Examination of genome-wide DNA methylation identified several differentially methylated regions, which were preferentially hypomethylated, in Fam60a-/- embryos. Our data suggest that Fam60a is required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation at specific gene promoters.

Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Desenvolvimento Embrionário/genética , Animais , Proteínas de Ligação a DNA/química , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Histona Desacetilases/química , Histona Desacetilases/genética , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Proteínas Repressoras/química , Proteínas Repressoras/genética , Complexo Correpressor Histona Desacetilase e Sin3
Genes Cells ; 21(7): 728-39, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27353389


Lrrc6 encodes a cytoplasmic protein that is expressed specifically in cells with motile cilia including the node, trachea and testes of the mice. A mutation of Lrrc6 has been identified in human patients with primary ciliary dyskinesia (PCD). Mutant mice lacking Lrrc6 show typical PCD defects such as hydrocephalus and laterality defects. We found that in the absence of Lrrc6, the morphology of motile cilia remained normal, but their motility was completely lost. The 9 + 2 arrangement of microtubules remained normal in Lrrc6(-/-) mice, but the outer dynein arms (ODAs), the structures essential for the ciliary beating, were absent from the cilia. In the absence of Lrrc6, ODA proteins such as DNAH5, DNAH9 and IC2, which are assembled in the cytoplasm and transported to the ciliary axoneme, remained in the cytoplasm and were not transported to the ciliary axoneme. The IC2-IC1 interaction, which is the first step of ODA assembly, was normal in Lrrc6(-/-) mice testes. Our results suggest that ODA proteins may be transported from the cytoplasm to the cilia by an Lrrc6-dependent mechanism.

Cílios/genética , Síndrome de Kartagener/genética , Proteínas/genética , Animais , Dineínas do Axonema/genética , Axonema/genética , Axonema/patologia , Cílios/patologia , Citoplasma/genética , Citoplasma/metabolismo , Proteínas do Citoesqueleto , Modelos Animais de Doenças , Dineínas/genética , Humanos , Síndrome de Kartagener/patologia , Camundongos , Camundongos Transgênicos , Mutação
J Cell Biol ; 204(2): 203-13, 2014 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-24421334


Axonemal dynein complexes are preassembled in the cytoplasm before their transport to cilia, but the mechanism of this process remains unclear. We now show that mice lacking Pih1d3, a PIH1 domain-containing protein, develop normally but manifest male sterility. Pih1d3(-/-) sperm were immotile and fragile, with the axoneme of the flagellum lacking outer dynein arms (ODAs) and inner dynein arms (IDAs) and showing a disturbed 9+2 microtubule organization. Pih1d3 was expressed specifically in spermatogenic cells, with the mRNA being most abundant in pachytene spermatocytes. Pih1d3 localized to the cytoplasm of spermatogenic cells but was not detected in spermatids or mature sperm. The levels of ODA and IDA proteins were reduced in the mutant testis and sperm, and Pih1d3 was found to interact with an intermediate chain of ODA as well as with Hsp70 and Hsp90. Our results suggest that Pih1d3 contributes to cytoplasmic preassembly of dynein complexes in spermatogenic cells by stabilizing and promoting complex formation by ODA and IDA proteins.

Proteínas Reguladoras de Apoptose/fisiologia , Dineínas do Axonema/metabolismo , Espermatozoides/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Axonema/metabolismo , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Fertilidade/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , RNA Mensageiro/metabolismo , Espermatozoides/ultraestrutura , Testículo/metabolismo