Disease relevance of Wnt7a

• The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout) [1].
• Members of the Wnt family of signaling molecules are important in cell specification and epithelial-mesenchymal interactions, and targeted gene deletion of Wnt-7a in mice results in complete absence of uterine glands and infertility [2].

High impact information on Wnt7a

• Wnt-7a mutant mice show a delay in the morphological maturation of glomerular rosettes and in the accumulation of synapsin I [3].
• Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis [4].
• Wnt7a, which is expressed in dorsal ectoderm, provides the signal required for Shh expression and formation of posterior structures [5].
• Wnt7a-deficient females are infertile because of abnormal development of the oviduct and uterus, both of which are Müllerian duct derivatives [6].
• Therefore, we propose that signalling by Wnt-7a allows sexually dimorphic development of the Müllerian ducts [6].

Biological context of Wnt7a

• We suggest a model whereby, in En1 mutants, ectopic ventral Wnt7a and/or Lmx1b expression leads to the transformation of ventral cells in the broadened AER to a more dorsal phenotype [7].
• Although Wnt7a down-regulation is transient after estrogenic exposure, subsequent morphologic changes became more pronounced during postnatal and adult life, suggesting that the female reproductive tract is permanently reprogrammed after exposure even to weak estrogenic compounds [8].
• Wnt7a is a suppressor of cell death in the female reproductive tract and is required for postnatal and estrogen-mediated growth [9].
• In addition, Wnt7a heterozygous mice were more sensitive to PCB exposure, revealing an important genetic predisposition to risks of environmental endocrine disruptors [8].
• Exposure to the potent estrogen-agonist diethylstilbestrol (DES) leads to an increase in cell proliferation in the uterus in wild-type as well as in mutant uteri, indicating that Wnt7a is not required in mediating cell proliferation [9].

Anatomical context of Wnt7a

• Sonic Hedgehog synergises with both Wnt1 and Wnt7a in explants from E8.5 paraxial mesoderm but not in explants from E9.5 embryos [10].
• Wnt4 is required for Müllerian duct initiation, whereas Wnt7a is required for subsequent differentiation [11].
• Wnt3a and Wnt7a were absent in the cell lines and tissues tested [12].
• A detailed genetic analysis of wild-type, En1 and Wnt7a mutant limb buds during AER development has delineated a role for En1 in normal AER formation [7].
• In situ hybridization experiments demonstrate that one of the isolated Wnt genes, Wnt7a, is broadly expressed in the embryonic telencephalon [13].

Associations of Wnt7a with chemical compounds

• The morphologic changes that were elicited by PCBs and DES were different immediately after exposure, suggesting that Wnt7a-independent pathways are also activated by one or both of these compounds [8].
• In contrast, we observe that Wnt7a mutant uteri display high levels of cell death in response to DES, whereas wild-type uteri display almost no cell death, revealing that Wnt7a plays a key role as a cell death suppressor [9].
• To test the hypothesis that PCBs act as weak estrogens, we injected neonatal mice with a commercial PCB mixture (Aroclor 1254) or with low levels of DES and measured effects of exposure on Wnt7a expression and uterine morphology [8].
• Pilot experiments showed a negative effect of Wnt-7a on the proliferation of three rodent chondrogenic cell lines, RCJ3.1(C5.18), CFK-2, and C1 [14].
• Based on analyses of the axonal cytoskeleton, a model is proposed in which Wnt-7a induces axonal remodelling by inhibiting glycogen synthase kinase-3 beta (GSK-3 beta), a serine/threonine kinase [15].

Physical interactions of Wnt7a

• En1 and Wnt7a interact with Dkk1 during limb development in the mouse [16].
• Overexpression of Wnt7a or of a stabilized form of beta-catenin in mouse cortical NPC cultures induced neuronal differentiation even in the presence of Fgf2, a self-renewal-promoting factor in this system [17].

Regulatory relationships of Wnt7a

• These results strongly support the idea that, in its normal domain of expression, En-1 represses Wnt7a-mediated dorsal differentiation by limiting the expression of Wnt7a to the dorsal ectoderm [18].
• Along the limb's dorsal-ventral axis, Wnt-5a is expressed in the ventral ectoderm and Wnt-7a in the dorsal ectoderm [19].
• Interestingly, Fz10 is expressed in the same regions as Wnt7a in the neural tube, limb buds, and Müllerian duct [20].
• We show that loss of function of Dishevelled-1 (Dvl1) mimics and enhances the Wnt7a phenotype in the cerebellum [21].

Other interactions of Wnt7a

• In contrast, expression of Drosophila en in the embryonic limbs of En1 mutants does not lead to repression of Wnt7a in the embryonic ventral ectoderm or full rescue of the embryonic dorsal/ventral patterning defects [22].
• We suggest that Fgfr2 is required for AER differentiation, as well as for En1 and Wnt7a expression [23].
• In addition, two previously described Wnt genes, Wnt5a and Wnt7a, were detected in RT-PCR products [24].
• Wnt-6 and Wnt-7a produced weak morphological changes [25].
• Wnt7a and Wnt7b mRNAs were expressed in three out of four cell lines (RL95-2, HEC-1-A and Ishikawa) [26].

References