Alternative titles; symbols
HGNC Approved Gene Symbol: WNT9B
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:46,833,189-46,886,738 (from NCBI)
Members of the WNT family, such as WNT9B, are structurally related genes that encode cysteine-rich secreted glycoproteins that act as extracellular signaling factors. All mammalian WNT proteins contain approximately 350 to 400 amino acids and have an N-terminal secretory signal peptide followed by a short domain of low sequence conservation and a large conserved domain that includes 22 cysteines, the relative spacing of which is exactly conserved in the majority of WNT proteins. WNT genes are implicated in a wide variety of biologic processes, including cell fate determination and patterning in early embryos and in cell growth and/or differentiation in certain adult mammalian tissues (Bergstein et al., 1997).
By PCR with degenerate primers, Bergstein et al. (1997) isolated 2 novel members of the WNT family in humans, WNT14 (WNT9A; 602863) and WNT15. WNT15 shows 53% amino acid identity to chicken Wnt14, 54% identity to human WNT14, and 65% identity to shark Wnt9. Bergstein et al. (1997) reported that, based on both an unusual cysteine spacing pattern and amino acid sequence comparison, WNT14 and WNT15 are more closely related to Drosophila Wnt4 (603490) and hagfish Wnt9 than to other members of the WNT family and may share common ancestry.
Qian et al. (2003) cloned mouse Wnt9b. The deduced 359-amino acid protein shares significant identity with the 331-amino acid human WNT9B protein, and both proteins contain all 23 cysteines conserved in Wnt proteins. Northern blot analysis of adult mouse tissues detected highest expression in kidney and lower expression in liver, brain, male preputial gland, and female mammary gland. No expression was detected in other adult tissues examined. In situ hybridization of 16.5-day mouse embryos detected Wnt9b in organs or tissues that normally undergo epithelial-mesenchymal induction during development, including vibrissae follicles, lung, nephros of the kidney, enamel epithelium of the developing tooth, and epithelium of the submandibular gland. High expression was also detected in brain, spinal cord, cranial ganglia, and olfactory epithelium. Lower expression was detected in intestinal epithelium, epidermis, and muscle, and little or no expression was detected in heart, liver, and cartilage.
By somatic cell hybridization, Bergstein et al. (1997) mapped the human WNT15 gene to chromosome 17. By interspecific backcross analysis, they mapped the mouse Wnt15 gene to distal chromosome 11. As this region is homologous to a segment of human 17q, Bergstein et al. (1997) verified the presence of WNT15 on 17q by PCR screening of human-hamster hybrid cell lines containing deleted portions of 17q. They refined the position to 17q21 within 125 kb of WNT3 (165330) by radiation hybrid and YAC mapping.
The urogenital system forms due to inductive interactions between the wolffian duct, its derivative the uretic bud, and their adjacent mesenchymes. These establish epithelial primordia within the mesonephric (embryonic) and metanephric (adult) kidneys and the mullerian duct, the anlage of much of the female reproductive tract. Carroll et al. (2005) found that Wnt9b was expressed in the inductive epithelia of mouse embryos. Using Wnt9b -/- mice, they showed that Wnt9b was essential for the development of mesonephric and metanephric tubules and caudal extension of the mullerian duct. Wnt9b -/- mice died within 24 hours of birth and displayed incompletely penetrant cleft lip and palate, vestigial kidneys, and lack of reproductive ducts. Further analysis of Wnt9b -/- mice showed that Wnt9b was required for the earliest inductive response in metanephric mesenchyme, and that it acted upstream of Wnt4. Carroll et al. (2005) concluded that canonical WNT signaling is a major pathway in the organization of the mammalian urogenital system.
Karner et al. (2009) found that disruption of Wnt9b signaling in mouse kidney via a hypomorphic Wnt9b allele or knockout of Wnt9b specifically in collecting duct stalks increased survival to postnatal day 30. However, these mutant mice showed postnatal development of renal cysts, with little normal epithelium remaining by postnatal day 30. Histologic and cytologic examination of wildtype and mutant kidneys revealed that Wnt9b was required for the oriented cell division and polarized elongation of renal tubule cells that occur postnatally and regulate kidney tubule diameter. Furthermore, Jnk2 (MAPK9; 602896) phosphorylation and the level of GTP-bound Rho (see RHOA; 165390), but not of Cdc42 (116952) or Rac (602048), were significantly decreased in mutant kidney, suggesting that Wnt9b signals through a noncanonical planar cell polarity pathway to regulate kidney tubule morphogenesis. Karner et al. (2009) concluded that WNT9B signals through the canonical WNT pathway to induce renal vesicle formation and through the noncanonical pathway to control renal tubule morphogenesis, and that defects in planar cell polarity, rather than cell growth, underlie cystogenesis in Wnt9b mutant mouse kidney.
Bergstein, I., Eisenberg, L. M., Bhalerao, J., Jenkins, N. A., Copeland, N. G., Osborne, M. P., Bowcock, A. M., Brown, A. M. C. Isolation of two novel WNT genes, WNT14 and WNT15, one of which (WNT15) is closely linked to WNT3 on human chromosome 17q21. Genomics 46: 450-458, 1997. [PubMed: 9441749] [Full Text: https://doi.org/10.1006/geno.1997.5041]
Carroll, T. J., Park, J.-S., Hayashi, S., Majumdar, A., McMahon, A. P. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev. Cell 9: 283-292, 2005. [PubMed: 16054034] [Full Text: https://doi.org/10.1016/j.devcel.2005.05.016]
Karner, C. M., Chirumamilla, R., Aoki, S., Igarashi, P., Wallingford, J. B., Carroll, T. J. Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nature Genet. 41: 793-799, 2009. [PubMed: 19543268] [Full Text: https://doi.org/10.1038/ng.400]
Qian, J., Jiang, Z., Li, M., Heaphy, P., Liu, Y.-H., Shackleford, G. M. Mouse Wnt9b transforming activity, tissue-specific expression, and evolution. Genomics 81: 34-46, 2003. [PubMed: 12573259] [Full Text: https://doi.org/10.1016/s0888-7543(02)00012-5]