Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract

Abstract

The Müllerian duct (MD) is the anlage of the oviduct, uterus and upper part of the vagina, the main parts of the female reproductive tract. Several wingless-type mouse mammary tumor virus (MMTV) integration site family member (Wnt) genes, including Wnt4, Wnt5a and Wnt7a, are involved in the development of MD and its derivatives, with Wnt4 particularly critical, since the MD fails to develop in its absence. We use, here, Wnt4EGFPCre-based fate mapping to demonstrate that the MD tip cells and the subsequent MD cells are derived from Wnt4+ lineage cells. Moreover, Wnt4 is required for the initiation of MD-forming cell migration. Application of anti-Wnt4 function-blocking antibodies after the initiation of MD elongation indicated that Wnt4 is necessary for the elongation as well, and consistent with this, cell culture wound-healing assays with NIH3T3 cells overexpressing Wnt4 promoted cell migration by comparison with controls. In contrast to the Wnt4 null embryos, some Wnt4monomeric cherry/monomeric cherry (Wnt4mCh/mCh) hypomorphic mice survived to adulthood and formed MD in ∼45% of cases. Nevertheless, the MD of the Wnt4mCh/mCh females had altered cell polarization and basement membrane deposition relative to the controls. Examination of the reproductive tract of the Wnt4mCh/mCh females indicated a poorly coiled oviduct, absence of the endometrial glands and an undifferentiated myometrium, and these mice were prone to develop a hydro-uterus. In conclusion, the results suggest that the Wnt4 gene encodes signals that are important for various aspects of female reproductive tract development.

wnt4apromotes female development and reproductive duct elongation in zebrafish

“…The wnt4a expression domain anterior to the eventual connection of the FDD and the genital orifice supports the hypothesis that tissues around the genital orifice likely secretes Wnt4a protein, and thus signal duct growth, elongation and connection to the exterior. Thus, as in mammals, Wnt4a may coodinate directional cell migration and extention of the reproductive duct (Prunskaite-Hyyryläinen et al . 2015).…”

Oviduct: roles in fertilization and early embryo development

“…The recent findings demonstrated that the morphological changes leading to a less coiled or uncoiled oviduct and formation of cysts within the oviduct can result in infertility. Wingless-type integration family member 4 (WNT4) signaling is critical for the development of the female reproductive tract, as female mice lacking Wnt4 expression showed a non-coiled oviduct that lacked folding (Prunskaite-Hyyrylainen et al 2016). Moreover, overexpression of Notch in the reproductive tract produced similar phenotypes whereby the oviduct failed to coil (Ferguson et al 2016).…”

The cell biology and molecular genetics of Müllerian duct development

“…This process involves a close interaction between epithelial cells and underlying mesenchyme (Figures 2 and 3). Important players in duct formation include the homeodomain transcription factors, EMX2, HOXA13, PAX2, and LIM1, and members of the Wnt family of secreted growth factors (namely, WNT4, WNT9B, and WNT7A) (Bouchard, Souabni, Mandler, Neubuser, & Busslinger, 2002;Kobayashi & Behringer, 2003;Kobayashi, Shawlot, Kania, & Behringer, 2004;Prunskaite-Hyyrylainen et al, 2016;Torres, Gomez-Pardo, Dressler, & Gruss, 1995) ( Figure 3). Although required for MD elongation, the first phases of development (specification and invagination) are thought to be independent of the WD (Carroll et al, 2005;Mullen & Behringer, 2014).…”