Mini Review

Wnt Signaling Associated Human Diseases

Yanqin Lu^1,2*, Xiuzhi Ren³, Yanzhou Wang⁴ and Jinxiang Han^1,2

¹ Key Laboratory for Biotech-Drugs Ministry of Health, Key Laboratory for Rare & Uncommon Diseases of Shandong Province, Shandong Medicinal Biotechnology Centre, Shandong Academy of Medical Sciences, Jinan, China

² School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, China

³ Department of Orthopedic Surgery, The People’s Hospital of Wuqing District, China

⁴ Department of Pediatric Surgery, Shandong Provincial Hospital, China

Submission: August 30, 2018; Published: September 10, 2018

*Corresponding author: Yanqin Lu, Shandong Academy of Medical Sciences, #18877 Jingshi Road, Jinan 250062, China

How to cite this article: Yanqin Lu, Xiuzhi Ren, Yanzhou Wang, Jinxiang Han. Wnt Signaling Associated Human Diseases. Nov Tech Arthritis Bone Res. 2018; 3(1): 555607. DOI: 10.19080/NTAB.2018.03.555607

Abstract

Wnts and their signaling cascades regulate a wide variety of biological processes and diseases. Aberrant canonical and non-canonical Wnt signaling components are pathogenic to various human genetic diseases and non-genetic diseases. Here, we review the spectrum of human diseases related with Wnt ligands, receptor, co-receptor, agonists, antagonists, transcript factor and other components in the signaling pathways. Results show that diseases related by Wnt signaling are predominated by genetic diseases, especially genetic skeletal disorders.

Keywords: Wnt Singaling Components; Genetic Skeletal Disorders; Non-Genetic Diseases

Abbrevations: Fzd: Frizzled; CK1: Casein kinase-1; GSK-3β: Glycogen synthase kinase-3β; APC APC: Adenomatous polyposis coli; TCF/LEF: T-cell factor/lymphoid enhancer factor; PCP: Planar cell polarity; Dsh/Dvl: Dishvelled; Pk: Prickle; DKK: Dickkopf; WIF: Wnt inhibitory factor; BMD: Bone Mass Density

Wnt Signaling Pathways

Wnt are secreted lipid-modified glycoproteins including 19 family members that transduces signal through one more of different signaling pathways. Wnt ligand binds to serial Frizzled (Fzd) receptor and LRP5/6 co-receptor, then destroy the destruction complex consisting of β-catenin, axin, casein kinase-1 (CK1), glycogen synthase kinase-3β (GSK-3β) and the adenomatous polyposis coli (APC). This leads to the translocation of β-catenin to the nucleus, where it binds to transcriptional factors T-cell factor/lymphoid enhancer factor (TCF/LEF) to induce the transcription of Wnt target genes. β-catenin-independent Wnt signaling pathways are multiple, Wnt/ planar cell polarity (PCP) pathway, utilizing small Rho-like GTPases, is related with polarization information for guiding tissue patterning and morphogenesis [1-5]. PCP is composed of core protein complexes and Fat/Daschsous (Ds)/Fj (Four-jointed) group. The core protein complexes include Frizzled, Flamingo (Fmi/Celsr), Van Gogh (Drosophila Vang or Stb/mammalian Vang), Dishvelled (Dsh/Dvl), Diego, and Prickle (Pk) [5-10]. Wnt/Ca2+ pathway, modulating intracellular Ca2+ level through Wnt5a and Fzd2-6 receptor as well as Ror1/2 co-receptor, as well as coreceptor Ror1/2 [11-15]. These signaling pathways are regulated by antagonists/agonists include secreted Frizzled related protein (SRFP) ,Dickkopf (DKK) family, Wnt inhibitory factor (WIF)1, sclerostin, Wntless, R-Spondin, and norrin. Wnt signaling pathway is vital to various biological processes, there’s no doubt that gene mutations of Wnt signaling cascades are causative to multiple human diseases.

Wnt Signaling and Human Diseases

As shown in Table 1. spectrum of human diseases related with Wnt signaling is broad, ranging from genetic diseases to complex diseases, but mainly for genetic diseases. Pathogenic genes for diseases are involved in the various Wnt ligands, receptor/coreceptor and regulators. The majority of gene mutations cause genetic diseases, in which genetic skeletal disorders are the main form [16-25].

Wnt Signaling and Human Skeletal Disorders

Components of Wnt signaling have been identified to have close relationship with high or low bone density. LRP5 has both loss or gain of function mutations that leads to low bone mass diseases including osteopetrosis (mim 607634, 166710) and osteoporosis-pseudoglioma syndrome (259770) [26-30]. high bone mass diseases of osteosclerosis/ hyperostosis, endosteal (mim 144750, Bone mineral density variability 1 (mim 601884) and van Buchem disease, type 2 (mim 607636). Sclerosteosis (SOST) mutation cause the high bone mass density (BMD) diseases of Van Buchem syndrome (mim 239100), sclerosteosis 1 (mim 269500) and craniodiaphyseal dysplasia (mim 122860) [31-35]. LRP4 mutation leads to type I sclerosteosis (mim 614305), which is also the disease with high BMD. Wnt1 is the pathogenic gene for type XV osteogenesis imperfect, and heterozygous of it mutation is responsible for early-onset osteoporosis. Nonsense variation of c.376C-T in LGR4, is strongly associated with low bone mass density and osteoporotic fractures. SFRP3 as the antagonist of Wnt signaling, is one of the susceptibility gene for osteoarthritis. Wnt5a (phenotype mim 180700) [36-40]. Fzd2, Ror2 (phenotype mim 268310), DVL1/3 (phenotype mim 616331, 616894) genes are all pathogenic genes for different Robinow syndrome types, which is highly related with Wnt/PCP signaling pathway. Wnt3 and Wnt7a are required for normal limb development and patterning [41-45].

Mutation of them leads to aberrant limb disorder (phenotype omim 273395, 276820, 228930). LRP4 (phenotype omim 212780) [46-55]. GPC6 (phenotype omim 258315) and SFRP4 (phenotype omim 265900) are all pathogenic gens for limb disorders. Furthermore, Homozygous mutation of RSPO2 is reported to cause humerofemoral hypoplasia with radiotibial ray deficiency [56-65]. (mim 618022) and tetraamelia syndrome 2 (mim 618021). Wnt10a/b are required for normal tooth development. Mutation of Wnt10a/b (phenotype mim 224750, 257980, 150400, 617073) and LRP6 receptor [66- 75]. (phenotype mim 603507), modulator of DKK1, KREMEN1 (phenotype mim 617392) and AXIN2 (phenotype mim 608615) are all causative to tooth agenesis and these genes are involved in canonical Wnt signaling. Meanwhile, receptor Fzd6 and agonist RSPO1/4 mutations of Wnt signaling are related with nail disorder such as claw-shaped [76-85]. nails (mim 614157), palmoplantar hyperkeratosis (mim 610644), anonychia congenital (mim 206800). Wnt 10b and ROR2, GP3 receptors in the Wnt signaling is involved in the diseases of foot malformation ectrodactyly (mim 225300), brachydactyly B1(mim 113000) and Simpson-Golabi-Behmel syndrome (mim 312870) [86].

Wnt Signaling and Non-Human Skeletal Disorders

Wnt signaling is implicated in various non-skeletal genetic disorders. Neurological diseases associated with Wnt signaling include Pitt-Hopkins syndrome (mim 610954), Sotos syndrome 3(mim 617169), mental retardation (mim 615075) and ZTTK syndrome (mim 617140), with pathogenic gene of TCF4, APC2, CTNNB1 and Son, respectively. Mutation of FZD4, NDP, LRP5 and CTNNB1 cause different type of exudative vitreoretinopathy (mim 133780, 305390, 601813, 617572) [87-90]. APC and RNF43 are pathogenic genes for brain tumor-polyposis syndrome (mim 175100) and sessile serrated polyposis cancer syndrome (mim 617108) correspondingly [91]. LRP6 and JUP gene are responsible for coronary artery disease (mim 610947), Naxos disease (mim 601214) and arrhythmogenic right ventricular dysplasia (mim 6115280). Wnt signaling is associated with wide spectrum of complex diseases, such as autism [92,93]. obesity, myocardial infarction, especially different types of cancers, with APC, CTNNB1, AXIN1/2, LEF1 and GPC3 from Wnt signaling cascades. Hence, various drugs have been implicated in the treatment of different cancers.

Conclusion

The review focuses on the relationship between Wnt signaling components and human diseases. Genetic and phenotypic heterogeneity is observed in both canonical and non-canonical Wnt signaling pathways. Skeletal dysplasia and cancers are the main types of Wnt signaling related diseases. The diseases of Wnt signaling preference provides the targets for treatment. Nowadays, many drugs targeting Wnt signaling is in preclinical or clinical periods for cancer, osteoporosis, neurodegenerative disease. Hopefully, the therapeutic of Wnt signaling related diseases will be successful in the future.

Acknowledgement

The work was supported by Grants-in-Aid from Shandong government (No. 2016ZDJS07A10, No.2016GSF201222), the State Major Infectious Disease Research Program (China Central Government, 2017ZX10103004-007).

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