Female mice with loss-of-function ITCH display an altered reproductive phenotype.
Female mice with loss-of-function ITCH display an altered reproductive phenotype.
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DOI：
10.1177/1535370215610656
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Richburg JH
中科院分区：
文献类型：
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作者：
Stermer AR;Myers JL;Murphy CJ;Di Bona KR;Matesic L;Richburg JH
解释E3连接酶ITCH在动物生理学中的作用的主要进展来自Itch功能丧失突变小鼠（Itch）的产生和鉴定。突变小鼠表现出以慢性皮炎为特征的自身免疫样表型，这归因于T细胞中ITCH靶蛋白（例如转录因子JUNB和CJUN）水平的增加。自身免疫性疾病也存在于人类中，其具有导致功能性ITCH蛋白丧失的Itch移码突变。最近的雄性瘙痒小鼠的表型分析显示精子产量减少，虽然杂交育种实验表明，当雄性瘙痒小鼠与野生型雌性交配时，产仔数没有差异。然而，当瘙痒的雌性与野生型雄性交配时，窝仔数确实减少。基于这些结果，对瘙痒小鼠的雌性生殖功能进行表征。妊娠第18.5天的胎儿发育分析、动情周期的细胞学评价、卵巢组织病理学分析和蛋白质分析用于研究瘙痒的生殖表型。妊娠第18.5天瘙痒胎仔的大体骨骼和软组织分析表明无大体发育畸形。与对照组相比，瘙痒雌性动物的着床部位减少，黄体减少，由于发情天数增加，发情周期长度增加。卵巢中原型ITCH靶点表达的改变未显示出来，这表明尚未确定的卵巢特异性ITCH底物的改变或与改变的免疫系统的相互作用可能是导致雌性生殖中断的原因。本报告表明E3连接酶，ITCH，在女性生殖的重要性。
Major progress in deciphering the role of the E3 ligase, ITCH, in animal physiology has come from the generation and identification of Itch loss-of-function mutant mice (itchy). Mutant mice display an autoimmune-like phenotype characterized by chronic dermatitis, which has been attributed to increased levels of ITCH target proteins (e.g. transcription factors JUNB and CJUN) in T cells. Autoimmune disorders also exist in humans with Itch frameshift mutations resulting in loss of functional ITCH protein. Recent phenotypic analysis of male itchy mice revealed reduced sperm production, although cross breeding experiments showed no difference in litter size when male itchy mice were bred to wild type females. However, a reduction in litter sizes did occur when itchy females were bred to wild type males. Based on these results, characterization of female reproductive function in itchy mice was performed. Developmental analysis of fetuses at gestational day 18.5, cytological evaluation of estrous cyclicity, histopathological analysis of ovaries, and protein analysis were used to investigate the itchy reproductive phenotype. Gross skeletal and soft tissue analysis of gestational day 18.5 itchy fetuses indicated no gross developmental deformities. Itchy females had reduced implantation sites, decreased corpora lutea, and increased estrous cycle length due to increased number of days in estrus compared to controls. Alterations in the expression of prototypical ITCH targets in the ovaries were not indicated, suggesting that an alteration in an as yet defined ovary-specific ITCH substrate or interaction with the altered immune system likely accounts for the disruption of female reproduction. This report indicates the importance of the E3 ligase, ITCH, in female reproduction.