VEZT

Last updated
VEZT
Identifiers
Aliases VEZT , VEZATIN, vezatin, adherens junctions transmembrane protein
External IDs MGI: 2143698 HomoloGene: 9739 GeneCards: VEZT
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_017599

NM_172538
NM_001304572
NM_001304575
NM_001304720

RefSeq (protein)

NP_001291501
NP_001291504
NP_001291649
NP_766126

Location (UCSC)n/a Chr 10: 93.94 – 94.04 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

VEZT is a gene located on chromosome 12 and encodes for the protein vezatin. Vezatin is a major component of the cadherin-catenin complex that is critical to the formation and maintenance of adherens junctions. [4] The protein is expressed in most epithelial cells and is crucial to the formation of cell-cell contact junctions. Mutations of the gene can lead to upregulation or downregulation of the protein which can have detrimental effects on physiological systems, particularly those involved in development.

Interactions

Role in Adherens Junctions

The protein vezatin has been shown to play a critical role in the maintenance and formation of adherens junctions in many epithelial cells. Adherens junctions are composed primarily of E-cadherin, alpha and beta catenins and other proteins such as actin and myosin. The junctions formed are vital in creating cell-cell contacts and do so via the interactions of all the different components. E-cadherins on separate cells use calcium based interactions to bind, whilst the catenins bind the cadherins to the actin cytoskeleton of each cell, thus creating the cadherin-catenin complex. Vezatin co-localises with E-cadherin at these cell-cell junctions suggesting that in fact it is involved within adherens junctions. [4] E-cadherin is an important transmembrane molecule in creating and facilitating adherens junctions, particularly in epithelial cells. Furthermore, vezatin does not appear at focal adhesion sites and does not co-localise with desmogleins, which are molecules present in desmosomes, suggesting it is solely responsible for interactions within the adherens junction. [4] Additionally, in cells lacking E-cadherin and thus unable to form cell-cell contacts, vezatin displayed a cytoplasmic distribution. [4] Another key component of this junction is the protein myosin VIIA and primarily its interaction with vezatin. Myosins are mechanochemical proteins which interact with actins and enzymatically convert ATP to ADP in order to facilitate a motor function. [5] Myosin VIIA is an unconventional member of the myosin family and is heavily expressed within ciliated epithelium such as that in the nose and the ear. [5] Myosin VIIA has a similar structure to all other myosins, with a motor, neck and actin-binding domain, but is unique due to its short tail domain. [5] Vezatin has been shown to interact with this tail domain due to co-localisation of both molecules in mouse inner-ear epithelial cells. [4] However, this interaction was only observed during cell-cell contact junctions, otherwise the proteins are dispersed through the cytoplasm in individual cells. [4] These results taken together suggest that vezatin plays a crucial role in the cadherin-catenin complex which is essential for cell-cell adhesion.

Role in Blastocyst Morphogenesis

The morphogenesis of a blastocyst is dependent on the formation of the trophectoderm, the first epithelial layer. [6] Like all other epithelium, the trophectoderm is composed of polarised cells with highly specialised adhesion complexes along the lateral sides of the cells. [6] This layer of cells is vital in the implantation of the embryo to the uterus and gives rise to majority of the extra-embryonic tissues. [6] In order for the proper physiological function of these cells and ultimately the proper development of the embryo, the adherens junctions between them must be properly developed. [7] VEZT codes for the protein vezatin which is an essential protein in the regulation and maintenance of these adherens junctions. However, most genes and subsequent protein release are determined by the combination of paternal and maternal DNA mixing. In the case of the early embryo, especially before compaction has started to occur, majority of the control is via the maternal genome. [6] Vezatin has been shown to appear in the mouse blastocyst as early as the 2-cell stage, suggesting that this protein is in fact under the maternal genome control. [8] Two isoforms of the protein however are evidenced later on at the 8-cell stage, suggesting that now the gene is under the control of the embryo itself. [8] [7] Furthermore, expression of vezatin has been shown to be linked with that of E-cadherin. Disruption of vezatin synthesis in the early embryo not only leads to lack of adherens junction formation, but also results in a strong reduction of E-cadherin protein present. [7] Vezatin itself could be involved in the regulation of the transcription of E-cadherin as it is seen within the nucleus of early embryonic cells. [8] Whilst there are several transcription factors that are associated with the repression of E-cadherin, it is unknown which is the novel target that is engaged when vezatin is also inhibited.

Role in Fertilisation

The process of spermatogenesis occurs in male mammals within the testis. [9] This is the process of rounded spermatocytes developing into elongating spermatozoa with a flagellum. [9] Spermatogenesis has two successive phases, one being spermiogenesis within the Sertoli cells of the testis and the other being maturation within the epididymis. [9] The adherens junctions in the Sertoli cells is one of the only epithelial cell-cell junction that lacks the expression of vezatin. Furthermore, the basal Sertoli-Sertoli cell junctions and the apical Sertoli-germ cell junctions contain myosin VIIA but lack its counterpart vezatin. [10] Myosin VIIA is almost always expressed with vezatin but the absence of this partnership within the testis is yet to be fully understood. However, vezatin has been shown to be expressed within the acrosomal region of the actual spermatozoa. [10] Vezatin is not found in the early spermatid but only appears when the formation of the acrosome occurs later on in the process of spermatogenesis. [10] The acrosome itself is divided into two functional domains, the inner acrosomal membrane which faces the nucleus and the outer acrosomal membrane which is in contact with the exterior surfaces of the sperm. This compartmentalisation of functions is vital to the fusion of the sperm with the egg as, it is the outer acrosomal domain which initiates the acrosome reaction, enabling the sperm to fuse. Vezatin is present in both these domains, but the translocation of vezatin from the inner to the outer membrane is unknown. Furthermore, vezatin is not expressed in the epididymal cells, thus vezatin cannot be added to the exterior membrane during maturation of the spermatozoa. [10] However, knowledge of the localisation of vezatin in this outer membrane and its known role in adherens junctions suggests that it plays a role in the fusion of the mammalian gametes during fertilisation. [10]

Role in Endometriosis

Endometriosis is a gynaecological disorder affecting 1 in 10 women in their reproductive years globally. [11] This disorder occurs when endometrial tissue which grows inside the lining of the uterus grows on the outer surface of the uterus. [12] The predominant symptoms of this are pelvic pain and infertility, however 25% of women who are inflicted with the disease may show none of these symptoms. [11] [12] Whilst the disease is usually non-fatal, it can have prolonged social and psychological effects on women and thus degrades their quality of life. [11] Whilst the causes of the disease are still unclear, a certain number of genes have been linked to being a contributing factor for the disease. Of these, mutations in the VEZT gene have been identified by various Genome-wide association studies (GWAS). [12] [13] [14] The VEZT gene is a complex gene, however it is known that the single nucleotide polymorphism (SNP) rs10859871 at locus 12q22 has been highly linked to being a genetic cause of endometriosis in women. [12] [14] An SNP is simply a variation that occurs in a single nucleotide in a specific region of a gene. Vezatin, the protein encoded by the VEZT gene is seen abundantly in endometrial and myometrial tissue, with localisation of the protein being both cytoplasmic and nuclear. [14] This result was concurrent with previous literature stating the prominent role of vezatin in the regulation and maintenance of adherens junctions. [13] This specific SNP is proven to cause an increase in vezatin expression within the endometrial cells, thus posing as a risk factor in the pathogenesis of endometriosis. [13] [14] Vezatin expression is also greater in ectopic endometrium as opposed to eutopic. [13] Furthermore, vezatin expression is significantly increased in glandular endometrium during the secretory phase of the menstrual cycle. [14] This result in conjunction with the finding that other adherens junction components also increase expression suggests that this process may be occurring in response to fluctuating progesterone levels. [14] However, the mechanism of increased vezatin expression leading to the formation of ectopic endometrial tissues is unknown. Furthermore, there is much more scientific study required to directly link mutations in the VEZT gene to a direct cause of endometriosis.

Related Research Articles

Blastulation

Blastulation is the stage in early animal embryonic development that produces the blastula. The blastula (from Greek βλαστός is a hollow sphere of cells surrounding an inner fluid-filled cavity. Embryonic development begins with a sperm fertilizing an egg cell to become a zygote, which undergoes many cleavages to develop into a ball of cells called a morula. Only when the blastocoel is formed does the early embryo become a blastula. The blastula precedes the formation of the gastrula in which the germ layers of the embryo form.

Cadherin

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that are important in the formation of adherens junctions to bind cells with each other. Cadherins are a class of type-1 transmembrane proteins, and they are dependent on calcium (Ca2+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred as the cadherin adhesome.

Cell junctions are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.

Catenin

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

Blood–testis barrier A physical barrier between the blood vessels and the seminiferous tubules of the animal testes

The blood–testis barrier is a physical barrier between the blood vessels and the seminiferous tubules of the animal testes. The name "blood-testis barrier" is misleading in that it is not a blood-organ barrier in a strict sense, but is formed between Sertoli cells of the seminiferous tubule and as such isolates the further developed stages of germ cells from the blood. A more correct term is the "Sertoli cell barrier" (SCB).

Adherens junction

Adherens junctions are protein complexes that occur at cell–cell junctions, cell–matrix junctions in epithelial and endothelial tissues, usually more basal than tight junctions. An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell or as spots of attachment to the extracellular matrix . Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells.

Beta-catenin

Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene.

Mesenchyme Type of connective tissue found mostly during the embryonic development of bilateral triploblast animals

Mesenchyme is a type of loosely organised animal embryonic connective tissue of undifferentiated cells that gives rise to blood and lymph vessels, bone, and muscle.

Implantation (human embryo) Stage of pregnancy

In humans, implantation is the stage of human reproduction at which the embryo adheres to the wall of the uterus. At this stage of prenatal development, the conceptus is called a blastocyst. Once this adhesion is successful, the female is considered to be pregnant and the embryo will receive oxygen and nutrients from the mother in order to grow.

The cells that give rise to the gametes are often set aside during embryonic cleavage. During development, these cells will differentiate into primordial germ cells, migrate to the location of the gonad, and form the germline of the animal.

Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem-cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem-cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to promote either self-renewal or differentiation to form new tissues. Several factors are important to regulate stem-cell characteristics within the niche: cell–cell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and the physicochemical nature of the environment including the pH, ionic strength and metabolites, like ATP, are also important. The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.

CDH2

N-cadherin, also known as Cadherin-2 (CDH2) or neural cadherin (NCAD) is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325. N-cadherin is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, N-cadherin is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of N-cadherin protein has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.

Tight junction protein 1

Zonula occludens-1 ZO-1, also known as Tight junction protein-1 is a 220-kD peripheral membrane protein that is encoded by the TJP1 gene in humans. It belongs to the family of zona occludens proteins, which are tight junction-associated proteins and of which, ZO-1 is the first to be cloned. It was first isolated in 1986 by Stevenson and Goodenough using a monoclonal antibody raised in rodent liver to recognise a 225-kD polypeptide in whole liver homogenates and in tight junction-enriched membrane fractions. It has a role as a scaffold protein which cross-links and anchors Tight Junction (TJ) strand proteins, which are fibril-like structures within the lipid bilayer, to the actin cytoskeleton.

P120 (protein)

p120, and called catenin delta-1 is a protein that in humans is encoded by the CTNND1 gene.

ARVCF

Armadillo repeat protein deleted in velo-cardio-facial syndrome is a protein that in humans is encoded by the ARVCF gene.

Catenin alpha-1

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

Gonocytes are the precursors of spermatogonia that differentiate in the testis from primordial germ cells around week 7 of embryonic development and exist up until the postnatal period, when they become spermatogonia. Despite some uses of the term to refer to the precursors of oogonia, it was generally restricted to male germ cells. Germ cells operate as vehicles of inheritance by transferring genetic and epigenetic information from one generation to the next. Male fertility is centered around continual spermatogonia which is dependent upon a high stem cell population. Thus, the function and quality of a differentiated sperm cell is dependent upon the capacity of its originating spermatogonial stem cell (SSC).

Cell polarity is a fundamental feature of many types of cells. Epithelial cells are one example of a polarized cell type, featuring distinct 'apical', 'lateral' and 'basal' plasma membrane domains. Epithelial cells connect to one another via their lateral membranes to form epithelial sheets that line cavities and surfaces throughout the animal body. Each plasma membrane domain has a distinct protein composition, giving them distinct properties and allowing directional transport of molecules across the epithelial sheet. How epithelial cells generate and maintain polarity remains unclear, but certain molecules have been found to play a key role.

PLEKHA7

PLEKHA7 is an adherens junction (AJ) protein, involved in the junction's integrity and stability.

The term Adhesome was first used by Richard Hynes to describe the complement of cell-cell and cell-matrix adhesion receptors in an organism and later expanded by Benny Geiger and co-workers to include the entire network of structural and signaling proteins involved in regulating cell-matrix adhesion.

References

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Further reading