Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects
Abstract
:1. Introduction
2. Neural Tube Formation: A Rapid, Multi-Step and Complex Process
3. Neural Tube Defects: What Could Go Wrong?
4. PCP Signaling: A Non-Canonical Branch of Wnt Signaling with Unresolved Mysteries
4.1. Non-Canonical Wnt/PCP Signaling: From Flies to Vertebrates
4.2. PCP and CE during Neural Tube Formation: Strong Evidence from Animal Models
4.3. PCP: Molecular Crosstalks to Other Processes and Pathways during Neurulation
5. PCP Signaling Genes in Human NTDs: What do We Know So Far?
5.1. Genetic Studies of PCP Signaling in Human NTDs
5.2. Are PCP Genes Major Culprits and/or Accomplices in the Complex Etiology of Human NTDs?
6. Conclusions and Challenges
Author Contributions
Funding
Conflicts of Interest
References
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Gene | NTD Cohort | Variant | Patient Description | Functional Validation | Reference |
---|---|---|---|---|---|
PCP core genes | |||||
ANKRD6 | 391 Italians and 82 French Canadians (14 cranial, 246 MMC, and 213 closed spinal NTDs) | p.Pro548Leu p.Arg587Gln p.Arg632His | MC LipoMS and MC CA | p.Pro548Leu and p.Arg632His were proven to be partially loss of function in activation of PCP signaling and inhibition of canonical Wnt pathway | [95] |
CELSR1 | 36 fetuses with CRS from US, France and England | p.Ala773Val p.Arg2438Gln p.Ser2964Leu p.Pro2983Ala | 1 CRS 1 CRS 2 CRS 2 CRS | All 4 variants significantly affected frequency of membrane localisation | [90] |
391 Italians and 82 French Canadians (same as above) | p.Arg541Trp p.Val551Met p.Gln834X p.Arg.836Cys p.Val1008Leu p.Asp1401Gly p.Thr1443Pro p.Arg1456Gln p.Arg1526Trp p.Arg1835Cys p.Arg2121Cys p.Ser2190Leu p.Ala2228Val p.Arg2359Cys p.Ser2963Thr2966del | MMC LMC MMC Lipoma TFT MMC LMMC CA MMC MMC LMMC Lipoma Lipoma LMC CA | Not conducted | [87] | |
192 American SB infants | p.Ala1023Gly p.Ile1124Met p.Thr1362Met p.Gly1410Arg Truncated protein (c.5050_5051 ins GT) p.Gly1825Ser Truncated protein (c.5719_5720 del TG) p.Gly2062Ser p.Arg2354Cys p.Arg2497Cys | All SB | Two truncated mutations disrupted CELSR1 membrane localization and its recruitment of Vangl2 to cell membrane. | [94] | |
352 Chinese patients (26 CRS, 73EC, 64AN, 3Ex, 255 SB, 1 unknown) | p.Pro870Leu | CRS | p.Pro870Leu was a gain-of-function variant in zebrafish overexpression and rescue experiments. It increased both PCP and canonical Wnt signalling | [99] | |
184 Chinese patients (36 AN,12 CRS, 32 EC, 2 Ex, 91 SB, 11 unknown) and 292 American patients (100% SB) | p.Arg714His p.Pro870Leu p.Thr875Ile p.Ala1019Ser p.Thr1086Met p.Arg1194His p.Gln1473Ter | AN, SB SB SB | Not conducted | [100] | |
510 Chinese patients (125 AN, 232 SB, 46 EC, 79 AN & SB, 1 AN & EC, 15 SB & EC, 4 AN & SB & EC, 8 unknown) | p. Arg769Trp p.Arg1057Cys p.Gly1122Ser p.Gln2924His | SB SB AN SB | Not conducted | [101] | |
CELSR2 | 352 Chinese patients (same as above) | p.Ser628Gly p.Thr2026Met p.Arg2153Gly p.Arg2480Cys p.Arg2015Gly fs*22 p.Phe2397Lys fs*584 | AN, SB SB EC SB CRS SB | p.Thr2026Met downregulated PCP signaling in a luciferase assay | [99,100] |
184 Chinese patients (same as above) | p.Ser628Gly p.Arg1990His p.Arg2015Gly fs*23 p.Thr2026His p.Arg2153Gly p.Arg2480Cys p.Arg2626Cys | Not conducted | [100] | ||
CELSR3 | 352 Chinese patients (same as above) | p.Gly194Val p.Val446Met p.Gly1754Asp | 1 AN, 1 SB CRS CRS | Not conducted | [99] |
184 Chinese patients (same as above) | p.Val446Met p.Ile1102Leu p.Arg1194His p.Arg1453Cys p.Gly1754Asp p.Gly1754Ser p.Val2584Gly p.Met2630Ile | Not conducted | [100] | ||
DVL2 | 473 Italian and French Canadian patients (same as above) | p.Ala53Val p.Glu620X (c.1801_1802ins) p.Tyr667Cys | Lipoma CA and TC MMC | Not conducted | [91] |
DVL3 | 184 Chinese patients (same as above) | p.Asp403Asn | SB | p.Asp403Asn disrupted DVL3 interaction with VANGL2, upregulated canonical Wnt signaling and down regulated non-PCP signaling | [100] |
510 Chinese patients (same as above) | p.Arg148Gln | AN | Not conducted | [101] | |
FZD6 | 473 Italian and French Canadian patients (same as above) | p.Cys615Ter p.Arg405Gln p.Arg511Cys p.Arg511His | MC MMC MMC CA | Not conducted | [89] |
PK1 | 810 patients: 421 Italian (11 cranial, 211 open spinal including 208 MMC, 199 closed spinal) and 389 Americans (4 cranial, 325 MMC, 60 closed spinal) | p.Ile69Thr p.Asn81His p.Thr275Met p.Val550Met p.Arg682Cys p.Ser739Phe p.Asp771Asn | DM MMC MMC MMC MMC MMC CA | p.Ile69Thr, p.Asn81His, p.Thr275Met and p.Arg682Cys acted as hypermorphic alleles in inducing CE defects in an overexpression assay in zebrafish; p.Arg682Cys antagonized the CE phenotype induced by the wild-type zpk1a in a dominant fashion | [85] |
VANGL1 | 137 Italian patients (80 MMC, 57 closed spinal) 7 French fetuses with CRS | p.Val239Ile p.Arg274Gln p.Met328Thr | CA MMC MMC, TC | p.Val239Ile abrogated interaction between VANGL1 and all three Dvl proteins; p.Val239Ile and p.Met328Thr failed to induce CE defects in overexpression assays and to rescue MO-induced CE defects in zebrafish | [81,104] |
673 patients: 284 Italians (11 cranial, 131 open spinal including 128 MMC, 142 closed spinal) and 389 Americans (4 cranial, 325 MMC, 60 closed spinal) | p.Ser83Ile p.Phe153Ser p.Arg181Gln p.Leu202Phe p.Ala404Ser | 3 TFT and TC TFT and TC MMC MMC CA | Not conducted | [83] | |
144 patients with open or closed NTDs from Slovakia, Romania and Germany | p.Gly205Arg p.Arg186His p.Arg173His | MMC TC and lipoma unknown | Not conducted | [88] | |
53 Italian patients (9 MMC, 44 closed spinal) | p.Alal187Val p.Arg517His p.His350 His | LipoMS MMC Cephalocele | Not conducted | [97] | |
VANGL2 | 66 English patients (21 CRS, 24 SB, 21 AN) | A 7 bp duplication detected 30 nucleotides into intron six (IVS6+30) | CRS | Not conducted | [82] |
163 Han Chinese fetuses (16 AN, 63 CRS, 8 EC, 4 HPS, 14 iniencephaly, 58 SB) | p.Ser84Phe p.Arg353Cys p.Phe437Ser | HPS AN with SB AN | p.Phe437Ser completely abrogated interaction with Dvl; p.Arg353Cys diminished but did not abolish this interaction | [84] | |
673 Italian and American patients (same as above) | p.Arg135Trp p.Arg177His p.Leu242Val p.Thr247Met p.Arg270His p.Arg482His | MMC DM 1MCS, 1MMC Lipoma Fibrolipoma CA and TC | Not conducted | [86] | |
PCP mediators | |||||
LRP6 | 285 Italian patients (6 closed cranial, 153 MMC, 126 closed spinal) | p.Tyr306His p.Thr373Cys p.Val1386Leu p.Thr1541Cys | MMC MMC EC CA | p.Tyr306His, p.Thr373Cys and p.Val1386Leu acted as hypomorphic alleles in activating canonical Wnt pathway and inhibiting PCP signaling | [93] |
192 American SB infants | p.Ala3Val p.Tyr544Cys p.Pro1482Leu p.Arg1574Leu | SB | p.Tyr544Cys lost its ability to bind MESD and its membrane localization and acted as a hypomorhic allele in activating canonical Wnt signalling; p.Arg1574Leu acted as a hypermorphic allele in activating canonical Wnt signaling; p.Pro1482Leu lost its ability to inhibit PCP signaling | [96] | |
PTK7 | 473 Italian and French Canadian patients (same as above) | p.Ile121Met p.Val291Ile p.Pro345Leu p.Gly348Ser p.Pro545Arg | MMC LipoMS MC MMC MMC | p.Ile121Met, p.Pro345Leu and p.Pro545Arg could act in a hypomorphic manner; p.Gly348Ser acted in a hypermorphic manner in overexpression assays in zebrafish;p.Pro545Arg affected stability of protein | [98,105] |
343 Chinese patients (70 AN, 19 CRS, 80 EC, 3 EX, 170 SB, 1 unknown) and 192 American SB infants | p.Asn128Ser p.Thr186Met p.Ala560Thr p.Arg630Ser p.Pro706Arg p.Tyr725Phe p.Gly765Arg p.Val775Met p.Arg790Leu | EX SB SB SB 2 AN, CRS, 2 SB SB 2 SB SB 2 SB, EC, AN | p.Arg630Ser affected protein stability and increased interaction with Dvl2; p.Thr186Met decreased PTK7 interactions with Dvl2 | [102] | |
510 Chinese patients (same as above) | p.Pro642Arg | SB | Not conducted | [101] | |
SCRIB1 | 52 fetuses with CRS (same as above) | p.Arg1535Gln | CRS | p.Arg1535Gln affected membrane localization of Scrib1 | [90] |
192 American SB infants | p.Ala366Thr p.Thr552Met p.Pro1043Leu p.Pro1332Leu p.Leu1520Arg | SB | p.Pro1043Leu, p.Pro1332Leu and p.Leu1520Arg significantly affected protein membrane localization | [92] | |
473 Italian and French Canadian patients (same as above) | p.Gly263Ser p.Pro649His p.Gln808His p.Arg1150Gln p.Thr1422Met | MMC CA MMC VS MMC | P.Gly263Ser and p.Gln808His significantly affected the subcellular localization of SCRIB1 and failed in rescuing the localization defect of Par-3 and Vangl1 caused by knockdown of Scrib1; P.Gln808His and p.Arg1150Gln abolished the interaction of Scrib1 with Vangl2. | [68] | |
510 Chinese patients (same as above) | p.Lys618Arg p.Gly644Val p.Arg1044Gln p.Gly1108Glu | SB SB AN SB | Not conducted | [101] |
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Wang, M.; de Marco, P.; Capra, V.; Kibar, Z. Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects. Cells 2019, 8, 1198. https://doi.org/10.3390/cells8101198
Wang M, de Marco P, Capra V, Kibar Z. Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects. Cells. 2019; 8(10):1198. https://doi.org/10.3390/cells8101198
Chicago/Turabian StyleWang, Mingqin, Patrizia de Marco, Valeria Capra, and Zoha Kibar. 2019. "Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects" Cells 8, no. 10: 1198. https://doi.org/10.3390/cells8101198
APA StyleWang, M., de Marco, P., Capra, V., & Kibar, Z. (2019). Update on the Role of the Non-Canonical Wnt/Planar Cell Polarity Pathway in Neural Tube Defects. Cells, 8(10), 1198. https://doi.org/10.3390/cells8101198