Targeted ablation of Wnt4 and Wnt5a in Mullerian duct mesenchyme impedes endometrial gland development and causes partial Mullerian agenesis
Targeted ablation of Wnt4 and Wnt5a in Mullerian duct mesenchyme impedes endometrial gland development and causes partial Mullerian agenesis
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DOI：
10.1093/biolre/ioy160
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发表时间：
2019-01-01
影响因子：
3.6
通讯作者：
Boerboom, Derek
中科院分区：
文献类型：
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作者：
St-Jean, Guillaume;Boyer, Alexandre;Boerboom, Derek
Wnt 4和Wnt 5a在雌性生殖道的胚胎发育以及成年小鼠的着床、蜕膜化和卵巢功能中具有明确的作用。虽然这些作用似乎重叠，但Wnt 5a和Wnt 4在这些组织中是否功能冗余尚未确定。我们通过将携带floxed等位基因的小鼠与Amhr 2（cre）品系杂交，同时灭活苗勒氏间充质和卵巢颗粒细胞中的Wnt 4和Wnt 5a来解决这一问题。而Wnt 4（flox/flox）; Amhr 2（cre/+）和Wnt 5a（flox/flox）; Amhr 2（cre/+）雌性小鼠的生育力降低了约50%，Wnt 4（flox/flox）; Wnt 5a（flox/flox）; Amhr 2（cre/+）小鼠几乎或完全不育。生育能力的丧失不是由于卵巢缺陷，因为血清卵巢激素水平、卵泡计数和排卵率与对照组相当。相反，在Wnt 4（flox/flox）; Wnt 5a（flox/flox）; Amhr 2（cre/+）小鼠中子宫异常，具有薄的子宫肌层和基质层，频繁的纤维化和子宫腺数量减少>90%，表明Wnt 4和Wnt 5a在子宫腺发生中的冗余或相加作用。Wnt 4（flox/flox）; Wnt 5a（flox/flox）; Amhr 2（cre/+）小鼠的生育力丧失归因于蜕膜化、着床和胎盘发育缺陷，其严重程度与腺体丧失的程度成比例。此外，三分之一的Wnt 4（flox/flox）; Wnt 5a（flox/flox）; Amhr 2（cre/+）雌性具有部分苗勒管衍生结构发育不全，但具有正常的输卵管和卵巢。总之，我们的研究结果表明，Wnt 4和Wnt 5a在女性生殖道的发育中发挥着多余的作用，并可能为某些女性苗勒管发育不全病例的病因学提供见解。
Wnt4 and Wnt5a have well-established roles in the embryonic development of the female reproductive tract, as well as in implantation, decidualization, and ovarian function in adult mice. Although these roles appear to overlap, whether Wnt5a and Wnt4 are functionally redundant in these tissues has not been determined. We addressed this by concomitantly inactivating Wnt4 and Wnt5a in the Mullerian mesenchyme and in ovarian granulosa cells by crossing mice bearing floxed alleles to the Amhr2(cre) strain. Whereas fertility was reduced by similar to 50% in Wnt4(flox/flox); Amhr2(cre/+) and Wnt5a(flox/flox); Amhr2(cre/+) females, Wnt4(flox/flox); Wnt5a(flox/flox); Amhr2(cre/+) mice were either nearly or completely sterile. Loss of fertility was not due to an ovarian defect, as serum ovarian hormone levels, follicle counts, and ovulation rates were comparable to controls. Conversely, the uterus was abnormal in Wnt4(flox/flox); Wnt5a(flox/flox); Amhr2(cre/+) mice, with thin myometrial and stromal layers, frequent fibrosis and a >90% reduction in numbers of uterine glands, suggesting redundant or additive roles of Wnt4 and Wnt5a in uterine adenogenesis. Loss of fertility in Wnt4(flox/flox); Wnt5a(flox/flox); Amhr2(cre/+) mice was attributed to defects in decidualization, implantation, and placental development, the severity of which were proportional to the extent of gland loss. Furthermore, a third of Wnt4(flox/flox); Wnt5a(flox/flox); Amhr2(cre/+) females had a partial agenesis of Mullerian duct-derived structures, but with normal oviducts and ovaries. Together, our results suggest that Wnt4 and Wnt5a play redundant roles in the development of the female reproductive tract, and may provide insight into the etiology of certain cases of Mullerian agenesis in women.