Wnt5a Regulates Embryonic Müllerian Duct Development Through the Non-Canonical Wnt PCP Pathway

TL;DR

This study shows that Wnt5a regulates the development of the Müllerian ducts in mice through the non-canonical Wnt PCP pathway, impacting reproductive tract anatomy.

Contribution

The study reveals new insights into Wnt5a's role in Müllerian duct development via the non-canonical Wnt PCP pathway.

Findings

Wnt5a-/- mice show dysregulation of the non-canonical Wnt PCP pathway in Müllerian ducts.

Wnt5a-/- Müllerian ducts have an overrepresentation of oviductal mesenchymal cells due to anterior uterine horn transformation.

Wnt5a is essential for both posterior and anterior Müllerian duct development in mice.

Abstract

Müllerian anomalies are anatomical variations of the female reproductive tract resulting from the incomplete development of the embryonic Müllerian ducts. The molecular mechanisms driving Müllerian duct development are complex and poorly understood, resulting in the largely unexplained aetiology of these conditions. WNT5A is a critical regulator of key developmental processes, including patterning, cell proliferation, and migration. Mutations of WNT5A have been associated with Robinow syndrome, a congenital condition characterized by skeletal and genital anomalies. In the mouse, WNT5A is necessary for the posterior development of the Müllerian duct, and ablation of Wnt5a results in vaginal agenesis. However, Wnt5a-/- uterine horns are hypoplastic and over 60% shorter than the wild type, suggesting specific functions in anterior Müllerian duct development. To better understand the role of Wnt5a, we performed single-cell RNA sequencing of developing Müllerian ducts. We found that the non-canonical Wnt PCP pathway was dysregulated in Wnt5a-/- mice. In addition, Wnt5a-/- Müllerian ducts were enriched in oviductal mesenchymal cells due to the transformation of the anterior uterine horns into oviducts. Our results indicate additional roles for Wnt5a during Müllerian duct development, prompting further investigations into uterine functions and anatomy in complex clinical cases of Müllerian anomalies including Robinow syndrome.

Figures