Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056, USA.
GEMpath Inc., Longmont, CO 80501-1846, USA.
Dis Model Mech. 2024 Mar 1;17(3). doi: 10.1242/dmm.050669. Epub 2024 Mar 28.
Mitogen-activated protein 3 kinase 1 (MAP3K1) has a plethora of cell type-specific functions not yet fully understood. Herein, we describe a role for MAP3K1 in female reproductive tract (FRT) development. MAP3K1 kinase domain-deficient female mice exhibited an imperforate vagina, labor failure and infertility. These defects corresponded with shunted Müllerian ducts (MDs), the embryonic precursors of FRT, that manifested as a contorted caudal vagina and abrogated vaginal-urogenital sinus fusion in neonates. The MAP3K1 kinase domain is required for optimal activation of the Jun-N-terminal kinase (JNK) and cell polarity in the MD epithelium, and for upregulation of WNT signaling in the mesenchyme surrounding the caudal MD. The MAP3K1-deficient epithelial cells and MD epithelium had reduced expression of WNT7B ligands. Correspondingly, conditioned media derived from MAP3K1-competent, but not -deficient, epithelial cells activated a TCF/Lef-luciferase reporter in fibroblasts. These observations indicate that MAP3K1 regulates MD caudal elongation and FRT development, in part through the induction of paracrine factors in the epithelium that trans-activate WNT signaling in the mesenchyme.
丝裂原活化蛋白激酶 3 激酶 1（MAP3K1）具有多种尚未完全理解的细胞类型特异性功能。在此，我们描述了 MAP3K1 在女性生殖道（FRT）发育中的作用。缺乏 MAP3K1 激酶结构域的雌性小鼠表现为阴道闭锁、分娩失败和不孕。这些缺陷与 Müllerian 管（MD）的分流相对应，MD 是 FRT 的胚胎前体，表现为尾部阴道扭曲和新生儿阴道-尿生殖窦融合缺失。MAP3K1 激酶结构域对于 MD 上皮细胞中 Jun-N-末端激酶（JNK）和细胞极性的最佳激活以及周围间质中 WNT 信号的上调是必需的。尾部 MD 中的细胞外基质。MAP3K1 缺陷的上皮细胞和 MD 上皮细胞中 WNT7B 配体的表达减少。相应地，源自 MAP3K1 功能完整但不是缺陷的上皮细胞的条件培养基可在成纤维细胞中激活 TCF/Lef-荧光素酶报告基因。这些观察结果表明，MAP3K1 调节 MD 尾部伸长和 FRT 发育，部分通过诱导上皮细胞中的旁分泌因子来转激活间质中的 WNT 信号。
