Morphogenesis of the female reproductive tract is regulated by the mesenchyme. However, the identity of the mesenchymal lineage that directs the morphogenesis of the female reproductive tract has not been determined. Using in vivo genetic cell ablation, we identified Amhr2+ mesenchyme as an essential mesenchymal population in patterning the female reproductive tract. After partial ablation of Amhr2+ mesenchymal cells, the oviduct failed to develop its characteristic coiling due to decreased epithelial proliferation and tubule elongation during development. The uterus displayed a reduction in size and showed decreased cellular proliferation in both epithelial and mesenchymal compartments. More importantly, in the uterus, partial ablation of Amhr2+ mesenchyme caused abnormal lumen shape and altered the direction of its long axis from the dorsal-ventral axis to the left–right axis (i.e. perpendicular to the dorsal-ventral axis). Despite these morphological defects, epithelia underwent normal differentiation into secretory and ciliated cells in the oviduct and glandular epithelial cells in the uterus. These results demonstrated that Amhr2+ mesenchyme can direct female reproductive tract morphogenesis by regulating epithelial proliferation and lumen shape without affecting the differentiation of epithelial cell types.
Morphogenesis of the female reproductive tract is regulated by the mesenchyme. However, the identity of the mesenchymal lineage that directs the patterning of the female reproductive tract has not been determined. Using in vivo genetic cell ablation, we identified Amhr2+ mesenchyme as an essential mesenchymal population in patterning the female reproductive tract. After partial ablation of Amhr2+ mesenchymal cells, the oviduct failed to develop its characteristic coiling due to decreased epithelial proliferation and tubule elongation during development. The uterus displayed a reduction in size and showed decreased cellular proliferation in both epithelial and mesenchymal compartments. More importantly, in the uterus, partial ablation of Amhr2+ mesenchyme caused abnormal lumen shape and altered the direction of its long axis from the dorsal-ventral axis to the left-right axis (i.e. perpendicular to the dorsal-ventral axis). Despite these morphological defects, epithelia underwent normal differentiation into secretory and ciliated cells in the oviduct and glandular epithelial cells in the uterus. These results demonstrated that Amhr2+ mesenchyme can direct female reproductive tract morphogenesis by regulating epithelial proliferation and lumen shape without affecting the differentiation of epithelial cell types.
Congenital unilateral defects of male reproductive tracts have been documented in men, suggesting the potential left-right asymmetry in male reproductive tract development. However, classic textbooks of endocrinology have been teaching us that the development of the paired male reproductive tract is governed by the universal action of the androgen receptor (Ar). During sexual differentiation, testis-derived androgens activate the Ar to promote the stabilization of the bilateral Wolffian ducts, the progenitor for the male reproductive tract. The Wolffian ducts then differentiate into the paired male reproductive tract organs, which include the epididymes, vas deferentes, and seminal vesicles. The Ar is expressed both in the epithelium and mesenchyme of the male reproductive tract during fetal development. Landmark tissue recombinant studies and the observation of normal morphology in the epithelium-specific Ar knockout mouse all support the notion that Ar action in the mesenchyme dictates the morphogenesis of the male reproductive tract. However, no genetic study has been performed to investigate the consequence of the loss of mesenchymal Ar on male reproductive tract development. To test the functional significance of the mesenchymal Ar, we designed a mesenchyme-specific Ar knockout mouse model (ARcKO) to ablate Ar specifically in the mesenchyme prior to the initiation of sexual differentiation. We performed immunohistochemistry of AR to confirm that Ar expression was absent in the mesenchyme while epithelial Ar remained intact in this ARcKO model. Based on the widely accepted notion that mesenchymal Ar regulates epithelial morphogenesis of the male reproductive tract, we expected to see abnormal patterning of the male reproductive tract. Indeed, the epididymis lost its characteristic coiling and became cystic. However, 40% of the 23 collected ARcKO males displayed these abnormalities on both horns; 43% and 17% displayed these abnormal phenotype solely on the left and right horn, respectively. This surprising observation might result from asynchronous activities of Cre on the left and right horns. However, when the Cre was crossed with a reporter (tdTomato), we observed comparable reporter expression on both horns at the onset of sexual differentiation of reproductive tracts. These observations suggest that the developmental programs in the morphogenesis of the left and right male reproductive tracts are asymmetrical and there could be a compensation mechanism for the loss of mesenchymal AR. We are currently in the process of comparing the left and the right horns in Ar knockout male mice to determine any biased signaling. Taken together, our study provides a unique model for not only studying congenital defects of male reproductive tracts but also for investigating the potential asymmetry in the masculinization program. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.
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