Beta-catenin biology in regeneration of uterine smooth muscle

描述（由申请人提供）：尽管子宫对于哺乳动物物种的繁殖和生存是必不可少的，但其与原始苗勒管的区别尚不清楚。我们假设2-连环蛋白在产后子宫发育中起主要作用，其功能失调可能是平滑肌瘤（最常见的妇科肿瘤）的潜在原因。传统的Wnt介导的信号转导是通过2-catenin的稳定及其向细胞核的易位以及与转录因子TCF/LEF的相互作用来调节靶基因的表达而发生的。此外，2-连环蛋白在连接粘附连接与肌动蛋白细胞骨架中起重要作用。我们正在研究2-catenin在子宫发育中的功能，并发现在小鼠子宫中靶向删除2-catenin会导致肌层脂肪逐渐取代平滑肌，并伴有动情周期。这些结果表明子宫中存在一种依赖于2-连环蛋白功能并受激素调节的再生细胞。我们建议通过以下方式继续这些研究：(1)鉴定行为类似骨骼肌再生卫星细胞的子宫平滑肌细胞。（二）确定形成子宫平滑肌的细胞来源。（三）确定肌脂表型是由于2-catenin的粘附还是核功能所致。这些研究的结果将提供对产后子宫发育的更好理解，并为子宫肌肉病变（如平滑肌瘤，通常称为子宫肌瘤）的病因提供线索。

DESCRIPTION (provided by applicant): Although the uterus is indispensable for propagation, and thus survival, of mammalian species, its differentiation from the primordial Mullerian ducts is not well understood. We hypothesize that 2-catenin plays a major role in postnatal uterine development and that its dysregulated function may be an underlying cause of leiomyomata, the most common gynecologic tumor. Conventional Wnt- mediated signal transduction occurs by the stabilization of 2-catenin and its translocation to the nucleus and interaction with the transcription factors TCF/LEF to modulate target gene expression. Additionally, 2-catenin plays an essential role in linking adherens junctions with the actin cytoskeleton. We are investigating the function of 2-catenin in uterine development and have found that targeted deletion of 2-catenin in mouse uterus leads to progressive replacement of smooth muscle with fat in the myometrium with estrous cycling. These results suggested that there is a regenerative cell in the uterus that is dependent on 2-catenin function and is hormonally regulated. We propose to continue these studies by- (I) Identifying the uterine smooth muscle cells that behave like the regenerative satellite cells in skeletal muscle. (II) Determining the source of the cells that contribute to uterine smooth muscle. (III) Determining whether the muscle-fat phenotype is due to the adhesion or the nuclear function of 2-catenin. The results of these studies will provide a better understanding of postnatal uterine development and should provide clues to the etiology of uterine muscle pathologies such a leiomyomata, which are more commonly known as uterine fibroids. More knowledge is needed about the process of uterine development and function, particularly when these processes are perturbed as with uterine fibroids, a significant indicator for hysterectomy. Understanding the mechanisms governing development of these benign tumors in the uterus should lead to safe, long-term medical therapies based on scientific rationales that could benefit thousands of women annually who might be spared surgery.