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首页> 外文期刊>Molecular and Cellular Biology >Genetic Ablation of the CDP/Cux Protein C Terminus Results in Hair Cycle Defects and Reduced Male Fertility
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Genetic Ablation of the CDP/Cux Protein C Terminus Results in Hair Cycle Defects and Reduced Male Fertility

机译：CDP / Cux蛋白C总站的遗传消融导致毛发周期缺陷和男性生育力下降

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摘要

Murine CDP/Cux, a homologue of the Drosophila Cut homeoprotein, modulates the promoter activity of cell cycle-related and cell-type-specific genes. CDP/Cux interacts with histone gene promoters as the DNA binding subunit of a large nuclear complex (HiNF-D). CDP/Cux is a ubiquitous protein containing four conserved DNA binding domains: three Cut repeats and a homeodomain. In this study, we analyzed genetically targeted mice (Cutl1tm2Ejn, referred to as ΔC) that express a mutant CDP/Cux protein with a deletion of the C terminus, including the homeodomain. In comparison to the wild-type protein, indirect immunofluorescence showed that the mutant protein exhibited significantly reduced nuclear localization. Consistent with these data, DNA binding activity of HiNF-D was lost in nuclear extracts derived from mouse embryonic fibroblasts (MEFs) or adult tissues of homozygous mutant (ΔC?/?) mice, indicating the functional loss of CDP/Cux protein in the nucleus. No significant difference in growth characteristics or total histone H4 mRNA levels was observed between wild-type and ΔC?/? MEFs in culture. However, specific histone genes (H4.1 and H1) containing CDP/Cux binding sites have reduced expression levels in homozygous mutant MEFs. Stringent control of growth and differentiation appears to be compromised in vivo. Homozygous mutant mice have stunted growth (20 to 50% weight reduction), a high postnatal death rate of 60 to 70%, sparse abnormal coat hair, and severely reduced fertility. The deregulated hair cycle and severely diminished fertility in Cutl1tm2Ejn/tm2Ejn mice suggest that CDP/Cux is required for the developmental control of dermal and reproductive functions.
机译：鼠CDP / Cux是果蝇Cut同源蛋白的同源物，可调节细胞周期相关基因和细胞类型特异性基因的启动子活性。 CDP / Cux与组蛋白基因启动子相互作用，是大型核复合物（HiNF-D）的DNA结合亚基。 CDP / Cux是一种普遍存在的蛋白质，包含四个保守的DNA结合结构域：三个Cut重复序列和一个同源结构域。在这项研究中，我们分析了基因突变的小鼠（Cutl1 tm2Ejn ，称为ΔC），它们表达的突变型 CDP / Cux 蛋白具有C末端的缺失，包括同源域。与野生型蛋白相比，间接免疫荧光表明突变蛋白显示出明显减少的核定位。与这些数据一致，HiNF-D的DNA结合活性在小鼠胚胎成纤维细胞（MEF）或纯合突变体（ΔC？/？）小鼠的成年组织的核提取物中丧失，表明其功能丧失CDP / Cux 蛋白在细胞核中的表达野生型和ΔC？/？ MEFs在生长特性或总组蛋白H4 mRNA水平上没有观察到显着差异。但是，包含CDP / Cux结合位点的特定组蛋白基因（H4.1和H1）在纯合突变型MEF中的表达水平降低。在体内严格控制生长和分化。纯合突变小鼠生长发育迟缓（体重减轻20％至50％），产后死亡率高至60％至70％，稀疏的被毛稀疏，生育能力严重降低。 Cutl1 tm2Ejn / tm2Ejn 小鼠的毛发循环失调，生育能力大大降低，这提示CDP / Cux是控制皮肤和生殖功能的必需条件。

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