DNA size: 6519 bp, DNA linear. Exon count: 6. This gene has 6 transcripts (splice variants), 56 orthologues, 5 paralogues.

Six transcript variants encoding different isoforms have been found for this gene (font: www.ensembl.org).
WNT10B-001 ENST00000301061.8: mRNA 2274 bp, protein 389 aa).
WNT10B-002 ENST00000203957.5: mRNA 1817 bp, protein 173 aa).
WNT10B-003 ENST00000407467.5: mRNA 1802 bp, protein 191 aa).
WNT10B-004 ENST00000413630.1: mRNA 623 bp, protein 132 aa).
WNT10B-005 ENST00000420388.1: mRNA 559 bp, protein 102 aa).
WNT10B-006 ENST00000475740.1: mRNA 429 bp, no protein encoded.

WNT10B
Hardiman et al., in 1997 isolated and characterized fort the first time the gene WNT10B that encodes a 389-amino acid protein with 96.6% sequence identity to mouse Wnt10b. They observed the expression pattern of WNT10B in different adult tissues with the highest levels found in heart, skeletal muscle and in several human cancer cell lines with elevated mRNA levels observed in HeLa (cervical cancer) cell ( Hardiman et al., 1997).
Dyregulation of WNT10B is implicated in different human pathologies as split hand/foot malformation (SHFM) and obesity (Aziz, 2014; VanCamp 2013).
Wnt Signaling
Wnt/β-catenin signaling pathway directs cell proliferation and cell fate during embryonic development and adult homeostasis. Moreover, deregulation of Wnt signaling is tightly linked to human disease, such as multiple forms of cancer and bone malformation (Clevers, 2006; Klaus and Birchmeier, 2008). Dysregulation of WNT signalling has been implicated in different types of cancers, (Lu et al, 2004; Simon et al, 2005; Cadigan and Nusse, 1997; Reya and Clevers, 2005), and the first direct connection between the Wnt pathway and human disease came in the early 1990s. Several studies pointed out the important role of the Wnt signaling in regulating mitotic divisions of hematopoietic stem cells (HSCs) (Reya et al., 2003). Wnt proteins were originally identified in Drosophila and mice (Nusslein-Volhard and Wieschaus, 1980; Nusse and Varmus, 1982), which were called Wingless (Wg) and Int1. Cadigan and Nusse identified 19 Wnt proteins that are secreted lipid-modified glycosylated signaling molecules, essential in various developmental processes (Cadigan and Nusse, 1997), acting both on the secreting cell and neighbouring cells and 10 frizzled receptors that can activate the canonical (Wnt/β-catenin), or non-canonical (Wnt/PCP or Wnt/Ca+) Wnt pathways. In the absence of Wnt ligand or presence of Wnt antagonists, the axin/adenomatous polyposis coli ( APC)/casein kinase 1 ( CSNK1A1)/glycogen synthase kinase 3 (GSK3) protein complex binds and phosphorylates β-catenin ( CTNNB1) resulting in ubiquitination and proteosomal degradation of β-catenin. The pathway is activated when a Wnt ligand binds to the transmembrane domain receptor of the Frizzled family (FZD) and its co-receptor low-density lipoprotein receptor-related protein 5 or 6 ( LRP5/( LRP6). Wnt proteins are characterized by an N-terminal signal sequence and by palmitoylation on a conserved cysteine residue, by the protein Porcupine ( PORCN). Wnt proteins are also characterized by cysteine residues and are glycosylated and lipid modified at two conserved residues, defining the hydrophobic profile of proteins. During the ligand receptor interaction, Wnt ligands bind to the extracellular N-terminal cysteine-rich domain of the Frizzled (FZD) receptor, which is related to the low density lipoprotein receptor-related protein 5 or 6 (LRP5/6). Therefore the cytoplasmic protein Dishevelled ( DVL1) is recruited to the receptor complex and then CK1 and GSK3β phosphorylates the cytoplasmic tail of LRP5/6. Then AXIN1, is recruited to the receptor complex and assembly of the destruction complex is disrupted. Active dephosphorilated β-catenin will accumulate in the cytoplasm to translocate into the nucleus, where it initiates transcription by activating T cell factor/lymphoid enhancer factor (TCF/ LEF1) transcription factors. When β-catenin is bound to the destruction complex is phosphorylated on Serine (Ser) 45 by CSNK1A1 (CK1α) which primes β-catenin for the sequential phosphorylation of Threonine (Thr) 42, Ser 39, and Ser 37 by GSK3β. This phosphorylation of β-catenin promotes the recognition by an E3 ubiquitin ligase, which leads to the ubiquitination and proteasomal degradation of β-catenin. In the absence of β-catenin TCF is linked to a transcriptional repressor complex with Groucho, a protein which is physically displaced by β- catenin (Clevers, 2006; Logan and Nusse, 2004; MacDonald et al., 2009; Mosimann et al., 2009; Staal and Clevers, 2005). Under unstimulated conditions, β-catenins are rapidly turned over by ubiquitination and degradation by the proteasome pathway. This requires phosphorylation of β-catenin by a "degradation complex" consisting of APC, Axin, GSK3, and CK1, followed by binding of BTRC (β -Trcp) (Rubinfeld et al., 1996; Munemitsu et al.; Willert and Jones, 2006). Signals induced by Wnt proteins interrupt the formation of the degradation complex, there by preventing the phosphorylation and destruction of β-catenin.

In human WNT10B is expressed in different tissues and organs, including bone marrow, whole blood, lymph node, thymus, cerebellum, brain, retina, spinal cord, heart, smooth muscle, skeletal muscle, small intestine, colon, adipocyte, kidney, liver, lung, pancreas, thyroid, salivary gland, adrenal gland, skin, ovary, uterus, placenta, cervix and prostate (http://www.genecards.org/cgi-bin/carddisp.pl?gene=WNT10B).
Aprelikova et al., showed that MIR148A is downregulated in 94% of cancer-associated fibroblasts (CAFs) compared with matched normal tissue fibroblasts (NFs) established from patients with endometrial cancer. They revealed that WNT10B is a direct target of MIR148A in CAFs from endometrial cancers and demonstrated that its upregulation in these cells increases tumor cell motility (Aprelikova et al., 2013)

WNT10B is a ligand secreted glycoprotein found mainly in the extracellular compartment. WNT10B proteins bind to the extracellular N-terminal cysteine-rich domain of the Frizzled (FZD) receptors, which is in a complex with the low density lipoprotein receptor-related protein 5 or 6 (LRP5/6). FZD receptors are seven-pass transmembrane receptors which have cycteine-rich domains (CRD) in their N-terminus. Through the CRD, FZD receptor binds Wnt ligands.

It was demonstrated that Wnt10b is expressed in cardiomyocytes and stored in the intercalated discs both in normal human and mouse hearts. Recently, Palk et al., evidenced that after injury, Wnt10b expression is upregulated in cardiomyocytes during the granulation tissue formation phase of cardiac repair, leading an increased angiogenesis by induction of KDR (vascular endothelial growth factor receptor 2, Vegfr-2) expression, formation of coronary-like vessels surrounded by vascular smooth muscle cells (vSMCs) via induction of ANGPT1 (angiopoietin-1) and cardiomyogenesis within scar tissue. The authors, highlighetd the role of Wnt10b in a cardiac repair by arteriole formation reducing the fibrosis and stimulating arteriole formation in NF-KB-dependent manner (Paik et al., 2015).
Davis et al., demonstrated that Wnt/beta-catenin signaling is a major regulator of mesenchymal stem cells fate (Davis et al., 2008). Matsushita et al., reported that Wnt10b/beta-catenin signaling is considered to act as a brake for adipogenic differentiation, suggesting an important role of Wnt10b as an endogenous regulator of adipogenesis. In addition, Matsushita et al., in their study demonstrated that AGTR2 (angiotensin II type 2 receptor) inhibits adipocyte differentiation of murine MSCs with Wnt10b/beta-catenin signaling, suggesting a strong interaction between Wnt10b/beta-catenin signaling and the the renin-angiotensin system (RAS), and providing important insights into the pathophysiology of obesity and obesity-related consequences (Matsushita et al., 2016).
Lei et al., evidenced in 2014 that in response to prolonged ectopic Wnt10b-mediated β-catenin activation, regenerating anagen hair follicles grew larger in size. These results were confirmed by Zhang et al., who provided the evidence that Wnt10b can induce hair follicle regeneration, in a time dependent manner, because a prolonged overexpression of Wnt10b induced an abnormal hair follicle regeneration by epidermal keratinocyte transformation, whereas transient overexpression of Wnt10b induces only hair follicle regeneration. They found that Wnt10b promoted the proliferation of hair follicle stem cells from 24 hours after Adenovirus vector AdWnt10b injection, and after seventy-two hours from AdWnt10b injection, cells outside of bulge area began to proliferate, providing the evidence that the overexpression of WNT10B might activate the hair follicle stem cells (HFSCs) inducing hair follicle regeneration (Lei et al., 2014; Zhang et al., 2016).
The role of Wnt10b in immune cells was first described in helper T cells (Hardiman et al., 1996), Wnt10b mRNA has been found during thymic development at embryonic day 13 (E13), and it is also found in the adult thymus (Balciunaite et al. 2002), suggesting that it should play a critical role, in an intrathymic T-cell development. Furthermore, it was demonstrated that in CD8⁺ T cells Wnt10b is induced by parathyroid hormone (PTH) in an osteoporosis model (Terauchi et al. 2009).
Wolf et al, in 2016 examined the interaction between PTH (parathyroid hormone) and WNT10B in periodontal regeneration, evidencing the interplay of T cells and human periodontal ligament (hPDL) cells via the WNT10B pathway as a modulating factor for the anabolic properties of the hormone in periodontal regeneration.
During last years, the research group of Miranda-Carboni showed that Wnt10b has an important role during the mammary gland development, bacause is expressed at the earliest time during differentiation of the mammary placode (Veltmaat et al. 2004;), suggesting that Wnt10b could be the placode specifier. Its specific role remains to be investigated. Moreover, Hamamoto et al highlighted that SMYD3upregulates WNT10B as a direct downstream gene and could promote breast carcinogenesis by directly regulating expression of the proto-oncogene WNT10B (Hamamoto et al., 2006).
Recently, Yu et al, in 2016 revealed a heterozygous missense mutation (c.632G>A [p.Arg211Gln]) in WNT10B in all family members affected by oligodontia, a severe form of tooth agenesis, is genetically and phenotypically a heterogeneous condition (Yu et al., 2016).
Finally, Beghini et al, in 2012 examining the role of Wnt signaling in acute myeloid leukemia, provided direct evidence of a ligand-dependent activation of the regeneration-associated Wnt pathway (Congdon et al, 2008), defining the term "regeneration" as the physiological phenomena of reconstitution from injury requiring rapid expansions of HSCs by reactivation of developmental pathways (Angers and Moon, 2009; Bowman, et al., 2012). They revealed that the ligand-dependent Wnt signaling is induced in AML through a diffuse expression and release of WNT10B, a hematopoietic stem cells regenerative-associated molecule (Beghini et al., 2012).

The WNT10B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, zebrafish, fruit fly, mosquito, and frog.