WNT4
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| Location (UCSC) | Chr 1: 22.12 – 22.14 Mb | Chr 4: 137 – 137.03 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
WNT4 is a secreted protein that, in humans, is encoded by the WNT4 gene, found on chromosome 1.[5][6] It promotes female sex development and represses male sex development. Loss of function may have consequences, such as female to male sex reversal.
Function
The
Pregnancy
WNT4 is involved in many features of pregnancy as a downstream target of
Sexual development
Early gonads
Gonads arise from the thickening of
WNT4 also interacts with
Female Sexual Development
Wnt4, is a growth factor and member of the Wnt gene family[9][10]that acts through frizzled receptors and intracellular signals which lead to transcriptional activation of a host of genes.[11] Wnt4 is involved in various developmental processes however, it is understood for its role in the development of the kidneys as well as in the development of the female reproductive tract and female secondary sex characteristics.[9] Wnt4 is expressed in the developing kidney, the mesonephros and the mesenchyme of the bipotential gonad,[9][12][13] and aids in development of the female reproductive tract. Specifically, by supporting oocyte development and regulating the formation of the mullerian duct, which will give rise to the oviduct, uterus, cervix and upper vagina. The growth factor also regulates steroidogenesis through upregulating genes such as Dax1, a gene expressed in the developing ovary and responsible for the inhibition of steroidogenic enzymes and ultimately the prevention of testis formation.[10][14][15] Models utilizing knockout mice have shown that the absence of Wnt4 results in the presence of steroidogenic enzymes, masculinization of female genitalia, failure of the wolffian duct to regress, absence of the mullerian duct as well as a decrease in oocyte numbers.[13] Studies utilizing the knockout mouse model have highlighted the importance of Wnt4 in female reproductive development.
Ovaries
WNT4 is required for female sex development. Upon secretion it binds to
Male sexual development
The absence of WNT4 is required for male sex development.
Kidneys
WNT4 is essential for nephrogenesis. It regulates
Muscles
WNT4 contributes to the formation of the
Lungs
WNT4 is also associated with lung formation and has a role in the formation of the
Clinical significance
Deficiency
Several mutations are known to cause loss of function in WNT4. One example is a heterozygous C to T transition in exon 2.
SERKAL syndrome
A disruption of WNT4 synthesis in XX humans produces
Mayer-Rokitansky-Kuster-Hauser Syndrome
WNT4 has been clearly implicated in the atypical version of Mayer-Rokitansky-Kuster-Hauser Syndrome found in XX humans. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12.[23] This occurrence reduces the intranuclear levels of β-catenin. In addition, it removes the inhibition of steroidogenic enzymes like 3β-hydroxysteriod dehydrogenase and 17α-hydroxylase. Patients usually have uterine hypoplasia, which is associated with biological symptoms of androgen excess. Furthermore, Müllerian abnormalities are often found.[23]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000162552 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036856 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: wingless-type MMTV integration site family".
- PMID 8168088.
- ^ PMID 21163860.
- ^ PMID 23095882.
- ^ .
- ^ .
- PMC 1219034.
- doi:10.1038/372679a0.
- ^ doi:10.1038/17068.
- .
- PMC 1226091.
- ^ PMID 18179883.
- ^ Gilbert S (2010). Developmental Biology (9th ed.). Massachusetts: Sinauer Associates.
- ^ PMID 22705479.
- PMID 16546160.
- ^ PMID 22253844.
- PMID 26321050.
- ^ PMID 16959810.
- ^ S2CID 33461252.
Further reading
- Uno S, Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T, Aoki D, Kamatani N, Hirata K, Nakamura Y (August 2010). "A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese". Nature Genetics. 42 (8): 707–10. S2CID 205356736.
- Kvell K, Varecza Z, Bartis D, Hesse S, Parnell S, Anderson G, Jenkinson EJ, Pongracz JE (May 2010). Hansen IA (ed.). "Wnt4 and LAP2alpha as pacemakers of thymic epithelial senescence". PLOS ONE. 5 (5): e10701. PMID 20502698.
- Kuulasmaa T, Jääskeläinen J, Suppola S, Pietiläinen T, Heikkilä P, Aaltomaa S, Kosma VM, Voutilainen R (October 2008). "WNT-4 mRNA expression in human adrenocortical tumors and cultured adrenal cells". Hormone and Metabolic Research. 40 (10): 668–73. S2CID 260167884.
- Philibert P, Biason-Lauber A, Rouzier R, Pienkowski C, Paris F, Konrad D, Schoenle E, Sultan C (March 2008). "Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study". The Journal of Clinical Endocrinology and Metabolism. 93 (3): 895–900. PMID 18182450.
- Jugessur A, Shi M, Gjessing HK, Lie RT, Wilcox AJ, PMID 20634891.
- Ravel C, Lorenço D, Dessolle L, Mandelbaum J, McElreavey K, Darai E, Siffroi JP (April 2009). "Mutational analysis of the WNT gene family in women with Mayer-Rokitansky-Kuster-Hauser syndrome". Fertility and Sterility. 91 (4 Suppl): 1604–7. PMID 19171330.
- Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM (December 2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". Journal of Bone and Mineral Research. 24 (12): 2039–49. PMID 19453261.
- Wan X, Ji W, Mei X, Zhou J, Liu JX, Fang C, Xiao W (February 2010). Riley B (ed.). "Negative feedback regulation of Wnt4 signaling by EAF1 and EAF2/U19". PLOS ONE. 5 (2): e9118. PMID 20161747.
- Memarian A, Hojjat-Farsangi M, Asgarian-Omran H, Younesi V, Jeddi-Tehrani M, Sharifian RA, Khoshnoodi J, Razavi SM, Rabbani H, Shokri F (December 2009). "Variation in WNT genes expression in different subtypes of chronic lymphocytic leukemia". Leukemia & Lymphoma. 50 (12): 2061–70. S2CID 38835813.
- Kelly JM, Kleemann DO, Rudiger SR, Walker SK (December 2007). "Effects of grade of oocyte-cumulus complex and the interactions between grades on the production of blastocysts in the cow, ewe and lamb". Reproduction in Domestic Animals = Zuchthygiene. 42 (6): 577–82. PMID 17976063.
- Flahaut M, Meier R, Coulon A, Nardou KA, Niggli FK, Martinet D, Beckmann JS, Joseph JM, Mühlethaler-Mottet A, Gross N (June 2009). "The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/beta-catenin pathway". Oncogene. 28 (23): 2245–56. S2CID 205531490.
- Altchek A, Deligdisch L (June 2010). "The unappreciated Wnt-4 gene". Journal of Pediatric and Adolescent Gynecology. 23 (3): 187–91. PMID 20060343.
- Yoshida T, Kitaura H, Hagio Y, Sato T, Iguchi-Ariga SM, Ariga H (April 2008). "Negative regulation of the Wnt signal by MM-1 through inhibiting expression of the wnt4 gene". Experimental Cell Research. 314 (6): 1217–28. PMID 18281035.
- O'Shaughnessy PJ, Baker PJ, Monteiro A, Cassie S, Bhattacharya S, Fowler PA (December 2007). "Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester". The Journal of Clinical Endocrinology and Metabolism. 92 (12): 4792–801. PMID 17848411.
- Vainio SJ (2003). "Nephrogenesis regulated by Wnt signaling". Journal of Nephrology. 16 (2): 279–85. PMID 12768078.
- Christopoulos P, Gazouli M, Fotopoulou G, Creatsas G (November 2009). "The role of genes in the development of Mullerian anomalies: where are we today?". Obstetrical & Gynecological Survey. 64 (11): 760–8. S2CID 10207018.
- Miyakoshi T, Takei M, Kajiya H, Egashira N, Takekoshi S, Teramoto A, Osamura RY (2008). "Expression of Wnt4 in human pituitary adenomas regulates activation of the beta-catenin-independent pathway". Endocrine Pathology. 19 (4): 261–73. S2CID 23734257.
- Drummond JB, Reis FM, Boson WL, Silveira LF, Bicalho MA, De Marco L (September 2008). "Molecular analysis of the WNT4 gene in 6 patients with Mayer-Rokitansky-Küster-Hauser syndrome". Fertility and Sterility. 90 (3): 857–9. PMID 18001722.
- Jääskeläinen M, Prunskaite-Hyyryläinen R, Naillat F, Parviainen H, Anttonen M, Heikinheimo M, Liakka A, Ola R, Vainio S, Vaskivuo TE, Tapanainen JS (April 2010). "WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival" (PDF). Molecular and Cellular Endocrinology. 317 (1–2): 106–11. S2CID 40887874.
- Mandel H, Shemer R, Borochowitz ZU, Okopnik M, Knopf C, Indelman M, Drugan A, Tiosano D, Gershoni-Baruch R, Choder M, Sprecher E (January 2008). "SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4". American Journal of Human Genetics. 82 (1): 39–47. PMID 18179883.
- Thrasivoulou C, Millar M, Ahmed A (December 2013). "Activation of intracellular calcium by multiple Wnt ligands and translocation of β-catenin into the nucleus: a convergent model of Wnt/Ca2+ and Wnt/β-catenin pathways". The Journal of Biological Chemistry. 288 (50): 35651–9. PMID 24158438.
External links
- GeneReviews/NCBI/NIH/UW entry on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
- OMIM entries on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
This article incorporates text from the United States National Library of Medicine, which is in the public domain.