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.
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]
WNT4 is involved in many 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]
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]
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]
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 FGFR2, 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]
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]
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]
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]
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]
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]
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. [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]
XY gonadal dysgenesis, also known as Swyer syndrome, is a type of defect hypogonadism in a person whose karyotype is 46,XY. Though they typically have normal vulvas, the person has functionless gonads, fibrous tissue termed "streak gonads", and if left untreated, will not experience puberty. The cause is a lack or inactivation of an SRY gene which is responsible for sexual differentiation. Pregnancy is often possible in Swyer syndrome with assisted reproductive technology. The phenotype is usually similar to Turner syndrome (45,X0) due to a lack of X inactivation. The typical medical treatment is hormone replacement therapy. The syndrome was named after Gerald Swyer, an endocrinologist based in London.
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
Müllerian agenesis, also known as Müllerian aplasia, vaginal agenesis, or Mayer–Rokitansky–Küster–Hauser syndrome, is a congenital malformation characterized by a failure of the Müllerian ducts to develop normally, resulting in an underdeveloped or missing uterus and variable degrees of vaginal hypoplasia of its upper portion. Müllerian agenesis is the cause in 15% of cases of primary amenorrhoea. Because most of the vagina does not develop from the Müllerian duct, instead developing from the urogenital sinus, along with the bladder and urethra, it is present even when the Müllerian duct is completely absent. Because ovaries do not develop from the Müllerian ducts, they are unaffected n and women with MRKH normal secondary sexual characteristics but are infertile due to the lack of a functional uterus. However, biological motherhood is possible through uterus transplantation or use of gestational surrogates.
Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein encoded by the SRY gene that is responsible for the initiation of male sex determination in therian mammals. SRY is an intronless sex-determining gene on the Y chromosome. Mutations in this gene lead to a range of disorders of sex development with varying effects on an individual's phenotype and genotype.
Vaginal atresia is a condition in which the vagina is abnormally closed or absent. The main causes can either be complete vaginal hypoplasia, or a vaginal obstruction, often caused by an imperforate hymen or, less commonly, a transverse vaginal septum. It results in uterovaginal outflow tract obstruction. This condition does not usually occur by itself within an individual, but coupled with other developmental disorders within the female. The disorders that are usually coupled with a female who has vaginal atresia are Mayer-Rokitansky-Küster-Hauser syndrome, Bardet-Biedl syndrome, or Fraser syndrome. One out of every 5,000 women have this abnormality.
XX male syndrome, also known as de la Chapelle syndrome, is a rare congenital intersex condition in which an individual with a 46,XX karyotype develops a male phenotype. Synonyms include 46,XX testicular difference of sex development, 46,XX sex reversal, nonsyndromic 46,XX testicular DSD, and XX sex reversal.
Intermediate mesoderm or intermediate mesenchyme is a narrow section of the mesoderm located between the paraxial mesoderm and the lateral plate of the developing embryo. The intermediate mesoderm develops into vital parts of the urogenital system.
Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.
Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system in humans. It is atypical development of gonads in an embryo. One type of gonadal dysgenesis is the development of functionless, fibrous tissue, termed streak gonads, instead of reproductive tissue. Streak gonads are a form of aplasia, resulting in hormonal failure that manifests as sexual infantism and infertility, with no initiation of puberty and secondary sex characteristics.
The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.
Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 gene.
Transcription factor SOX-9 is a protein that in humans is encoded by the SOX9 gene.
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.
Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.
Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.
Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene.
R-spondin-1 is a secreted protein that in humans is encoded by the RSPO1 gene, found on chromosome 1. In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal. Furthermore, it promotes canonical WNT/β catenin signaling.
Wingless-type MMTV integration site family, member 2, also known as WNT2, is a human gene.
Müllerian duct anomalies are those structural anomalies caused by errors in Müllerian duct development during embryonic morphogenesis. Factors that precipitate include genetics, and maternal exposure to teratogens.
WNT4 deficiency is a rare genetic disorder that affects females and it results in the underdevelopment and sometimes absence of the uterus and vagina. WNT4 deficiency is caused by mutations of the WNT4 gene. Abnormally high androgen levels are found in the blood and can initiate and promote the development of male sex characteristics. This is seen as male pattern of hair growth on the chest and face. Those with this genetic defect develop breasts but do not have their period. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct syndrome. Some women who have an initial diagnosis of MRKH have later been found to have WNT4 deficiency. Most women with MRKH syndrome do not have genetic mutations of the WNT4 gene. The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. WNT4 deficiency can cause significant psychological challenges and counseling is recommended.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
