WNT4

WNT4
Identifiers
AliasesWNT4, SERKAL, WNT-4, Wnt family member 4
External IDsOMIM: 603490 MGI: 98957 HomoloGene: 22529 GeneCards: WNT4
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1p36.12Start22,117,305 bp[1]
End22,143,969 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

54361

22417

Ensembl

ENSG00000162552

ENSMUSG00000036856

UniProt

P56705

P22724

RefSeq (mRNA)

NM_030761

NM_009523

RefSeq (protein)

NP_110388

NP_033549

Location (UCSC)Chr 1: 22.12 – 22.14 MbChr 4: 137.28 – 137.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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 can have serious consequences, such as female to male sex reversal.

Function

The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and embryogenesis.[5]

Pregnancy

WNT4 is involved in a couple features of pregnancy as a downstream target of BMP2. For example, it regulates endometrial stromal cell proliferation, survival, and differentiation.[7] These processes are all necessary for the development of an embryo. Ablation in female mice results in subfertility, with defects in implantation and decidualization. For instance, there is a decrease in responsiveness to progesterone signaling. Furthermore, postnatal uterine differentiation is characterized by a reduction in gland numbers and the stratification of the luminal epithelium.[7]

Sexual development

Early gonads

Gonads arise from the thickening of coelomic epithelium, which at first appears as multiple cell layers. They later commit to sex determination, becoming either female or male under normal circumstances. Regardless of sex, though, WNT4 is needed for cell proliferation.[8] In mouse gonads, it has been detected only eleven days after fertilization. If deficient in XY mice, there is a delay in Sertoli cell differentiation. Moreover, there is delay in sex cord formation. These issues are usually compensated for at birth.[8]

WNT4 also interacts with RSPO1 early in development. If both are deficient in XY mice, the outcome is less expression of SRY and downstream targets.[8] Furthermore, the amount of SOX9 is reduced and defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.[8]

Ovaries

WNT4 is required for female sex development. Upon secretion it binds to Frizzled receptors, activating a number of molecular pathways. One important example is the stabilization of β catenin, which increases the expression of target genes.[9] For instance, TAFIIs 105 is now encoded, a subunit of the TATA binding protein for RNA polymerase in ovarian follicle cells. Without it, female mice have small ovaries with less mature follicles. In addition, the production of SOX9 is blocked.[10] In humans, WNT4 also suppresses 5-α reductase activity, which converts testosterone into dihydrotestosterone. External male genitalia are therefore not formed. Moreover, it contributes to the formation of the Müllerian duct, a precursor to female reproductive organs.[9]

Male sexual development

The absence of WNT4 is required for male sex development. FGF signaling suppresses WNT4, acting in a feed forward loop triggered by SOX9. If this signaling is deficient in XY mice, female genes are unrepressed.[11] With no FGF2, there is a partial sex reversal. With no FGF9, there is a full sex reversal. Both cases are rescued, though, by a WNT4 deletion. In these double mutants, the resulting somatic cells are normal.[11]

Kidneys

WNT4 is essential for nephrogenesis. It regulates kidney tubule induction and the mesenchymal to epithelial transformation in the cortical region. In addition, it influences the fate of the medullary stroma during development. Without it, smooth muscle α actin is markedly reduced. This occurrence causes pericyte deficiency around the vessels, leading to a defect in maturation. WNT4 probably functions by activating BMP4, a known smooth muscle differentiation factor.[12]

Muscles

WNT4 contributes to the formation of the neuromuscular junction in vertebrates. Expression is high during the creation of first synaptic contacts, but subsequently downregulated.[13] Moreover, loss of function causes a 35 percent decrease in the number of acetylcholine receptors. Overexpression, however, causes an increase. These events alter fiber type composition with the production of more slow fibers. Lastly, MuSK is the receptor for WNT4, activated through tyrosine phosphorylation. It contains a CRD domain similar to Frizzled receptors.[13]

Lungs

WNT4 is also associated with lung formation and has a role in the formation of the respiratory system. When WNT4 is knocked out, there are many problems that occur in lung development. It has been shown that when WNT4 is knocked out, the lung buds formed are reduced in size and proliferation has greatly diminished which cause underdeveloped or incomplete development of the lungs. It also causes tracheal abnormalities because it affects the tracheal cartilage ring formation. Lastly, the absence of WNT4 also affects the expression of other genes that function in lung development such as Sox9 and FGF9.[14]

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.[15] This causes an arginine to cysteine substitution at amino acid position 83, a conserved location. The formation of illegitimate sulfide bonds creates a misfolded protein, resulting in loss of function. In XX humans, WNT4 now cannot stabilize β-catenin.[15] Furthermore, steroidogenic enzymes like CYP17A1 and HSD3B2 are not suppressed, leading to an increase in testosterone production. Along with this androgen excess, patients have no uteruses. Other Müllerian abnormalities, however, are not found. This disorder is therefore distinct from classic Mayer-Rokitansky-Kuster-Hauser syndrome.[15]

SERKAL syndrome

A disruption of WNT4 synthesis in XX humans produces SERKAL syndrome. The genetic mutation is a homozygous C to T transition at cDNA position 341.[9] This causes an alanine to valine residue substitution at amino acid position 114, a location highly conserved in all organisms, including zebrafish and Drosophila. The result is loss of function, which affects mRNA stability. Ultimately it causes female to male sex reversal.[9]

Mayer-Rokitansky-Kuster-Hauser Syndrome

WNT4 has been clearly implicated in the atypical version of Mayer-Rokitansky-Kuster-Hauser Syndromefound in XX humans. A genetic mutation causes a leucine to proline residue substitution at amino acid position 12.[16] 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.[16]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162552 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036856 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. 1 2 "Entrez Gene: wingless-type MMTV integration site family".
  6. ↑ Huguet EL, McMahon JA, McMahon AP, Bicknell R, Harris AL (May 1994). "Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue". Cancer Research. 54 (10): 2615–21. PMID 8168088.
  7. 1 2 Franco HL, Dai D, Lee KY, Rubel CA, Roop D, Boerboom D, Jeong JW, Lydon JP, Bagchi IC, Bagchi MK, DeMayo FJ (April 2011). "WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse". FASEB Journal. 25 (4): 1176–87. doi:10.1096/fj.10-175349. PMC 3058697. PMID 21163860.
  8. 1 2 3 4 Chassot AA, Bradford ST, Auguste A, Gregoire EP, Pailhoux E, de Rooij DG, Schedl A, Chaboissier MC (December 2012). "WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad". Development. 139 (23): 4461–72. doi:10.1242/dev.078972. PMID 23095882.
  9. 1 2 3 4 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. doi:10.1016/j.ajhg.2007.08.005. PMC 2253972. PMID 18179883.
  10. ↑ Gilbert, Scott (2010). Developmental Biology (9th ed.). Massachusetts: Sinauer Associates.
  11. 1 2 Jameson SA, Lin YT, Capel B (October 2012). "Testis development requires the repression of Wnt4 by Fgf signaling". Developmental Biology. 370 (1): 24–32. doi:10.1016/j.ydbio.2012.06.009. PMID 22705479.
  12. ↑ Itäranta P, Chi L, Seppänen T, Niku M, Tuukkanen J, Peltoketo H, Vainio S (May 2006). "Wnt-4 signaling is involved in the control of smooth muscle cell fate via Bmp-4 in the medullary stroma of the developing kidney". Developmental Biology. 293 (2): 473–83. doi:10.1016/j.ydbio.2006.02.019. PMID 16546160.
  13. 1 2 Strochlic L, Falk J, Goillot E, Sigoillot S, Bourgeois F, Delers P, Rouvière J, Swain A, Castellani V, Schaeffer L, Legay C (2012). "Wnt4 participates in the formation of vertebrate neuromuscular junction". PLoS One. 7 (1): e29976. doi:10.1371/journal.pone.0029976. PMC 3257248. PMID 22253844.
  14. ↑ Caprioli A, Villasenor A, Wylie LA, Braitsch C, Marty-Santos L, Barry D, Karner CM, Fu S, Meadows SM, Carroll TJ, Cleaver O (October 2015). "Wnt4 is essential to normal mammalian lung development". Developmental Biology. 406 (2): 222–34. doi:10.1016/j.ydbio.2015.08.017. PMID 26321050.
  15. 1 2 3 Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ (January 2007). "WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report". Human Reproduction. 22 (1): 224–9. doi:10.1093/humrep/del360. PMID 16959810.
  16. 1 2 Sultan C, Biason-Lauber A, Philibert P (January 2009). "Mayer-Rokitansky-Kuster-Hauser syndrome: recent clinical and genetic findings". Gynecological Endocrinology. 25 (1): 8–11. doi:10.1080/09513590802288291. PMID 19165657.

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. doi:10.1038/ng.612. PMID 20601957.
  • 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. doi:10.1371/journal.pone.0010701. PMC 2872673. 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 = Hormon- Und Stoffwechselforschung = Hormones et Metabolisme. 40 (10): 668–73. doi:10.1055/s-2008-1078716. PMID 18553255.
  • 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. doi:10.1210/jc.2007-2023. PMID 18182450.
  • Jugessur A, Shi M, Gjessing HK, Lie RT, Wilcox AJ, Weinberg CR, Christensen K, Boyles AL, Daack-Hirsch S, Nguyen TT, Christiansen L, Lidral AC, Murray JC (July 2010). Reitsma PH, ed. "Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia". PLoS One. 5 (7): e11493. doi:10.1371/journal.pone.0011493. PMC 2901336. 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. doi:10.1016/j.fertnstert.2008.12.006. 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. doi:10.1359/jbmr.090524. PMC 2791518. 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. doi:10.1371/journal.pone.0009118. PMC 2817739. 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. doi:10.3109/10428190903331082. PMID 19863181.
  • 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. doi:10.1111/j.1439-0531.2006.00823.x. 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. doi:10.1038/onc.2009.80. PMID 19421142.
  • Altchek A, Deligdisch L (June 2010). "The unappreciated Wnt-4 gene". Journal of Pediatric and Adolescent Gynecology. 23 (3): 187–91. doi:10.1016/j.jpag.2009.10.001. 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. doi:10.1016/j.yexcr.2008.01.002. 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. doi:10.1210/jc.2007-1690. 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. doi:10.1097/OGX.0b013e3181bea203. PMID 19849868.
  • 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. doi:10.1007/s12022-008-9048-9. PMID 19034702.
  • 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. doi:10.1016/j.fertnstert.2007.07.1319. 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". Molecular and Cellular Endocrinology. 317 (1–2): 106–11. doi:10.1016/j.mce.2009.11.013. PMID 19962424.
  • 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. doi:10.1016/j.ajhg.2007.08.005. PMC 2253972. 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. doi:10.1074/jbc.M112.437913. PMC 3861617. PMID 24158438.

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