Fig. 9. Role and regulation of Wnt genes during FRT morphogenesis and estrogenic response. (A) Schematic comparison of Hoxa code and Hoxa mutant phenotypes with Wnt5a and Wnt7a mutant phenotypes in the FRT. During fetal development, all the Hoxa genes, Wnt7a and Wnt5a are expressed all along the anteroposterior axis of the FRT (not shown). At birth, domains of Hoxa genes expression start to regionalize along the anteroposterior axis of the FRT (see left diagram). The regionalization of Hoxa10 to the uterine horn slightly precedes regionalization of Wn7a and Wnt5a also to the uterine horns that occur a few days after birth. The Hoxa10 mutant phenotype presents a bona fide homeotic transformation of the anterior 25% of the uterine horn into an oviduct-like structure. Loss of Hoxa11, or one allele of each Hoxa10 and Hoxa11 genes, or loss of Wnt7a affects primarily the uterine horns; however, Wnt7a phenotype can also affect the oviduct and the vagina. Loss of Hoxa13 or Wnt5a affects the caudal growth of the Müllerian ducts and the growth of the genital tubercle (not shown). (B) Postnatal uterine morphogenesis. Wnt7a is required for correct epithelial organization, the radial growth and patterning of the adjacent mesenchymal cells, and the organization of the smooth muscle layers. Wnt7a is required for maintenance (dotted arrows) of high levels of Wnt5a, Wnt4, Hoxa10 and Hoxa11 genes. Wnt5a signals cooperate with an unknown factor X to allow Wnt7a downregulation during gland formation (this study). (C) Wnt5a-dependant and Wnt5a-independent uterotrophic response to DES. DES binding to stromal Esr1, downregulates Wnt7a in the epithelium through a factor X that is functional or present only when Wnt5a is expressed. The factor X could be the same or different to the factor X required for Wnt7a repression during glandulargenesis. DES, through factor X, represses the levels of Hoxa10 and Hoxa11 in the stroma either directly or through repression of Wnt7a. Correct Wnt5a dependant downregulation of Wnt7a and Hoxa genes by prolonged estrogenic signal may be involved in the stimulation of glandulargenesis, fluid retention by the stroma and possibly preparation of the uterine wall for embryo implantation.