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Wnt-5a is one member of the so-called Wnt family of proteins (Nusse et al, 1991), identified by Gavin et al (1990) by virtue of sequence homology to Wnt-1. Clark et al (1993) have cloned the human gene shown shown that Wnt-5a is expressed only in neonatal heart and lung. Human Wnt-5a shows over 99 % amino acid sequence homology with mouse Wnt-5a, and 90 % with Xenopus laevis Wnt-5a (Lejeune et al, 1995).

He et al (1997) have shown that human frizzled-5 is a receptor for Wnt-5a. Kawasaki et al (2007) have reported that Wnt-5a is a natural ligand of frizzled-3. Mikels and Nusse (2006) have shown that Wnt-5a uses frizzled-4 as a receptor. Kurayoshi et al (2007) have shown that post-translational palmitoylation and glycosylation of Wnt-5a are necessary for receptor signaling. Other receptors of Wnt-5a has been identified as the tyrosine kinase ror2 and ryk.

Yang et al (2003) have reported that Wnt5a, together with Wnt5b, coordinates chondrocyte proliferation and differentiation. Both factors regulate the transition between different chondrocyte zones independently of the Indian hedgehog / parathyroid hormone-related peptide negative feedback loop. Wnt-5a and Wnt-11 signaling through distinct non-canonical Wnt pathways have opposing effects on type II collagen expression by chondrocytes (Ryu and Chun, 2006).

Sen et al (2001) have suggested that Wnt-5a - frizzled-5 signaling may contribute to the activated state of synoviocytes in rheumatoid arthritis. A blockade of Wnt-5a signaling in these cells diminishes IL6 and IL15. A blockade of the frizzled-5 receptor exerts similar effects and also reduces RANKL expression.

Nishizuka et al (2008) have reported that Wnt-4 and Wnt-5a have crucial roles in adipogenesis as positive regulators. The inhibition of Wnt-4 or Wnt-5a expression prevents the accumulation of triacylglycerol and decreases the expression of adipogenesis-related genes.

Developmental role of Wnt-5a

Wnt-5a plays a role in planar cell polarity, i.e., the polarization of cells within the plane of a cell sheet (Qian et al, 2007).

An analysis of early human embryos at 28-42 days of gestation shows that Wnt-5a transcripts are not restricted to the developing brain and limbs but are observed also in the mesenchyme bordering the pharyngeal clefts and pouches and in the developing gonads and kidneys. A relatively high expression in the celomic epithelium and in the precursors of follicles and seminiferous tubules suggest a role for Wnt-5a in germ cell differentiation (Danielson et al, 1995).

Wnt-5a regulates a pathway common to many structures whose development requires extension from the primary body axis. One function of Wnt-5a is to regulate the proliferation of progenitor cells (Yamaguchi et al, 1999). Dealy et al (1993) have reported that Wnt-5a is expressed in the apical ectodermal ridge which directs outgrowth of limb mesoderm and is involved in pattern formation along the proximodistal axis in chicken development. Misexpression of Wnt-5a in the limb bud results in truncation of long bones because of retarded chondrogenic differentiation. (Kawakami et al, 1999).

Allgeier et al (2008) have studied prostrate development in knock-out mice lacking expression of Wnt-5a and have concluded that Wnt-5a participates in prostatic bud patterning by restricting mouse ventral prostate development.

Loscertales et al (2008) have suggested a role of Wnt-5a in mid-pulmonary patterning (during alveolarization). Wnt-5a regulates sonic hedgehog and FGF-10 signaling during lung development (Li et al, 2005). Wnt-5a knock-out mice show distinct abnormalities in distal lung morphogenesis as manifested by distinct truncation of the trachea and overexpansion of the distal respiratory airways. Epithelial and mesenchymal cell compartments in the lungs of these mice exhibit increased cell proliferation. Mutant lungs are characterized by overexpansion of the distal airways and inhibition of lung maturation (Li et al, 2002).

Roarty and Serra (2007) have reported that Wnt-5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth.

Nunes et al (2007) have reported an involvement of Wnt-5a during early mice tooth development.

Schleiffarth et al (2007) have reported that mutations in Wnt-5a cause persistent truncus arteriosus, a form of congenital heart disease characterized by the lack of septation of the cardiac outflow tract.

Listyorini D, Yasugi (2006) have reported that Wnt-5a plays a role in the development of the glandular stomach in the chicken embryo, identifying Wnt-5a as a mesenchymal factor that regulates the differentiation of the proventricular epithelium.

Mericskay et al (2004) have reported that Wnt-5a is required for proper epithelial-mesenchymal interactions in the uterus.

Cha et al (2004) have reported that mice deficient in Wnt-5a display abnormal morphology in the dorsal part of the developing pituitary. Specification of the hormone producing cell types of the mature anterior pituitary gland occurs appropriately. A primary role of Wnt-5a in the developing pituitary gland thus appears to be the establishment of the shape of the gland.

Role of Wnt-5a in immunity and inflammation

Pereira et al (2008) have reported that Wnt-5a is expressed in macrophages and detected in sera and bone marrow macrophages of patients with severe sepsis. Expression of Wnt-5a is most highly induced by a combination of LPS andIFN-gamma and suppressed by activated protein C and IL10. A functional Wnt-5a - frizzled-5 signaling pathway is essential for macrophage inflammatory activation.

Blumenthal et al (2006) have implicated the Wnt-5a signaling system in bridging innate and adaptive immunity to infections. They have shown that human peripheral blood mononuclear cells express the Wnt-5a receptor Frizzled-5. Functional studies show that Wnt-5a and frizzled-5 regulate the microbially induced IL12 response of antigen-presenting cells and IFN-gamma production by mycobacterial antigen-stimulated T-cells.

Christman et al (2008) have implicated Wnt-5a in atherosclerosis, an inflammatory disease involving the accumulation of macrophages in the intima, demonstrating Wnt-5a expression in murine and human atherosclerotic lesions.

Role of Wnt-5a in apoptosis

Torii et al (2008) have reported that Wnt-5a inhibits cell death by apoptosis induced by serum deprivation in primary cultures of human dermal fibroblasts.

Role of Wnt-5a in angiogenesis

Cheng et al (2008) have reported that Wnt5a-mediated non-canonical Wnt signaling regulates endothelial cell proliferation. Blocking this pathway suppresses endothelial cell proliferation, migration, and monolayer wound closure. Wnt-5a gene expression is upregulated when endothelial cells are treated with a cocktail of inflammatory cytokines. Non-canonical Wnt signaling, therefore, plays a role in regulating endothelial cell growth and possibly in angiogenesis. Endothelial cells cultured in the presence of Wnt-1 display increased canonical Wnt signaling, proliferation, and capillary stability in vitro. Wnt-5a, which primarily signals via an alternate non-canonical Wnt pathway, decreases both cell number and capillary length (Goodwin et al, 2007).

Masckauchan et al (2006) have reported that Wnt-5a is expressed in human primary endothelial cells and is expressed in murine vasculature at several sites in mouse embryos and tissues. Wnt-5a induces endothelial cell proliferation and enhances cell survival under serum-deprived conditions. The Wnt5a-mediated proliferation is blocked by Frizzled-4 extracellular domain. Wnt-5a expression enhances capillary-like network formation, whereas reduction of Wnt-5a expression decreases network formation. Reduced Wnt-5a expression inhibits endothelial cell migration. Screening for Wnt5a-regulated genes in cultured endothelial cells shows that Wnt-5a promotes angiogenesis by upregulating expression of MMP-1 and TIE-2, a receptor for angiopoietins.

Role of Wnt-5a in hematopoiesis

Murdoch et al (2003) have shown that Wnt-5a augments primitive hematopoietic development in vivo and represents an in vivo regulator of hematopoietic stem cell function in humans.

Nemeth et al (2007) have reported that non-canonical Wnt-5a inhibits canonical Wnt signaling in hematopoietic stem cells mediated by Wnt-3a. This suppresses Wnt3a-mediated alterations in gene expression associated with hematopoietic stem cell differentiation. Wnt5a increases short- and long-term hematopoietic stem cell repopulation by maintaining hematopoietic stem cells in a quiescent G0 state of the cell cycle. Wnt-5a thus appears to regulate hematopoiesis by the antagonism of the canonical Wnt pathway, resulting in a pool of quiescent hematopoietic stem cells.

Role of Wnt-5a in neurogenesis

Yu et al (2006) have reported that Wnt-5a is involved in the differentiation and proliferation of postnatal neural progenitor cells. Parish et al (2008) have shown that Wnt-5a improves the differentiation and functional integration of stem cell-derived dopamine neurons. Wnt-5a induces the differentiation of immature primary midbrain precursors into tyrosine hydroxylase-positive dopaminergic neurones (Schulte et al, 2005). Castelo-Branco et al (2006) have reported that ventral midbrain glia, but not cortical glia, secrete high levels of Wnt-5a, which is partially responsible for the differentiation of cortical or ventral midbrain Nurr-1 precursors into tyrosine hydroxylase-positive neurons. Keeble et al (2006) have have reported that Wnt-5a, acting through its receptor ryk, is a key guidance receptor in the establishment of the corpus callosum. Zhang et al (2007) have implicated Wnt-5a in axon differentiation in cultured embryonic rat hippocampal neurons.

Bodmer et al (2009) have reported that Wnt-5a rapidly induces axon branching and has a long-term effect on promoting axon extension. Loss of Wnt-5a function shows that it is necessary for NGF dependent axonal branching and growth, but not survival, in vitro. Knock-out mice lacking expression of Wnt-5a display reduced innervation of NGF expressing target tissues, and a subsequent increase in neuronal apoptosis, in vivo.

Association of Wnt-5a expression and cancers

Olson and Gibo (1998) have concluded that Wnt-5a is an important regulator of cell growth and differentiation and its loss of expression leads to cell transformation.

Saitoh and Katoh (2002) have reported that upregulation of Wnt-5a in several types of human cancer expressing the receptor frizzled-5 might lead to more malignant phenotype.

Liang et al (2003) have reported that Wnt-5a negatively regulates B-cell proliferation in a cell-autonomous manner. Wnt-5a hemizygous mice develop myeloid leukemias and B-cell lymphomas that are clonal in origin and display loss of Wnt-5a function in tumor tissues. The analysis of human primary leukemias reveals deletion of the Wnt-5a gene and/or loss of Wnt-5a expression in a majority of the patient samples, demonstrating that Wnt-5a suppresses hematopoietic malignancies. Ying et al (2007) have reported that Wnt-5a is epigenetically silenced in hematologic malignancies and inhibits leukemia cell growth as a tumor suppressor. Wnt-5a hypermethylation correlates with lower disease-free survival in patients with acute lymphoblastic leukaemia (Roman-Gomez et al, 2007).
Lejeune et al (1995) have reported overexpression of Wnt-5a in human breast cancer. Loss of Wnt-5a is associated with early relapse in invasive ductal breast carcinomas (Jšnsson et al, 2002). Leandersson et al (2006) have reported a lack of Wnt-5a protein expression in invasive human breast tumors.
Saitoh et al (2002) have reported frequent upregulation of Wnt-5a in primary gastric cancer. Kurayoshi et al (2006) have reported that Wnt-5a expression is correlated with advanced stages and poor prognosis of gastric cancer. Wnt-5a stimulates cell migration and invasion in gastric cancer cells, which is suppressed by blocking Wnt-5a expression.
Weeraratna et al (2002) have reported that Wnt-5a expression in human melanoma biopsies directly correlates with increasing tumor grade. Blocking of the Wnt-5a frizzled-5 signaling pathway inhibits cellular invasion. Da Forno et al (2008) have reported that cytoplasmic Wnt-5a increases with melanoma progression and strong expression is associated with poor outcome. Expression of Wnt-5a in uveal melanoma cells is higher in tumors from patients with shorter survival (Zuidervaart et al, 2007). Witze et al (2008) have reported that Wnt-5a controls cell orientation, polarity, and directional movement in response to positional cues from chemokine gradients in a melanoma cell line. Dissanayake et al (2007) have shown that Wnt-5a mediates motility in melanoma cells via the inhibition of metastasis suppressors and the initiation of epithelial-mesenchymal transition.
Blanc et al (2005) have reported that low expression of Wnt-5a gene is associated with high-risk neuroblastoma. Retinoic acid reverses the aberrant negative regulation of Wnt-5a in metastatic neuroblasts (Blanc et al, 2005). Yu et al (2007) have indicated that Wnt5a signaling is an important regulator in the proliferation of human glioma cells, with overexpression increasing proliferation and downregulation of expression having the opposite effect.
Dejmek et al (2005) have reported that the expression of Wnt-5a in primary Dukes B colon cancer tissue constitutes a good prognostic marker for longer survival, which can be explained by the ability of Wnt-5a to impair tumor cell migration and thus reduce invasiveness and metastasis. Wnt-5a is frequently inactivated in colorectal cancer by tumor-specific methylation (Ying et al, 2008).
Iozzo et al (1995) have reported aberrant Wnt-5a gene expression levels in lungs, breast, and prostate carcinomas and in melanomas.
Zhuang et al (1999) have reported that overexpression of Wnt-5a may be involved in oncogenesis of urinary malignancies.
Taki et al (2003) have reported upregulation of Wnt-5a as a possible marker of the malignant phenotype of human squamous cell carcinoma.
Kremenevskaja et al (2005) have reported increased expression of Wnt-5a in thyroid carcinomas.
Huang et al have reported that overexpression of Wnt-5a may produce more aggressive non-small-cell lung cancer, especially in squamous cell carcinomas, during tumor progression.
Ripka et al (2007) have found upregulation of Wnt-5a expression during early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias lesions and in invasive pancreatic adenocarcinomas.
Wang et al (2007) have suggested that an epigenetic mechanism involving hypomethylation regulates Wnt-5a expression in prostate cancer.
Liu et al (2008) have reported that Wnt-5a protein expression is frequently lost in hepatocellular carcinoma.

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