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CELSR3

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Target id: 180

Nomenclature: CELSR3

Systematic Nomenclature: ADGRC3

Family: Adhesion Class GPCRs

Contents:

Gene and Protein Information Click here for help
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 3312 3p21.31 CELSR3 cadherin EGF LAG seven-pass G-type receptor 3 20
Mouse 7 3301 9 F2 Celsr3 cadherin, EGF LAG seven-pass G-type receptor 3 17
Rat 7 3313 8q32 Celsr3 cadherin, EGF LAG seven-pass G-type receptor 3 10
Previous and Unofficial Names Click here for help
ADGRC3 (adhesion G protein-coupled receptor C3) | MEGF2 | multiple epidermal growth factor-like domains 2
Database Links Click here for help
Specialist databases
GPCRdb celr3_human (Hs), celr3_mouse (Mm), celr3_rat (Rn)
Other databases
Alphafold Q9NYQ7 (Hs), Q91ZI0 (Mm), O88278 (Rn)
Ensembl Gene ENSG00000008300 (Hs), ENSMUSG00000023473 (Mm), ENSRNOG00000053889 (Rn)
Entrez Gene 1951 (Hs), 107934 (Mm), 83466 (Rn)
Human Protein Atlas ENSG00000008300 (Hs)
KEGG Gene hsa:1951 (Hs), mmu:107934 (Mm), rno:83466 (Rn)
OMIM 604264 (Hs)
Pharos Q9NYQ7 (Hs)
RefSeq Nucleotide NM_001407 (Hs), NM_080437 (Mm), NM_031320 (Rn)
RefSeq Protein NP_001398 (Hs), NP_536685 (Mm), NP_112610 (Rn)
UniProtKB Q9NYQ7 (Hs), Q91ZI0 (Mm), O88278 (Rn)
Wikipedia CELSR3 (Hs)
Associated Protein Comments
Extracellular and transmembrane interactors: ADGRC3 [13], Frizzled-3 [15], dystroglycan [9].
Agonist Comments
No ligands identified: orphan receptor.
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Other - See Comments
Comments:  Principal transduction is potentially through Gαq/11 by calcium imaging [13].
References: 
Tissue Distribution Click here for help
Brain
Species:  Human
Technique:  EST
References:  2
Central nervous system. Celsr3 is primarily expressed in differentiating neural cells after they exit the mitotic cycle, and drops to almost negligible levels when cell maturation is complete.
Species:  Mouse
Technique:  in situ hybridisation.
References:  7,11-12,14,17-19,21,23
Pancreas
Species:  Mouse
Technique:  in situ hybridisation.
References:  3
Testis
Species:  Rat
Technique:  in situ hybridisation.
References:  1
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Elevated intracellular calcium levels upon homotypic CELS3 interactions
Species:  Rat
Tissue:  Hippocampal neurons
Response measured:  Elevated intracellular calcium
References:  13
Physiological Functions Click here for help
Inhibition of neurite outgrowth.
Species:  Rat
Tissue:  Hippocampus.
References:  13
Physiological Consequences of Altering Gene Expression Click here for help
Mice with receptor knockout exhibit defects in pancreatic β-cell differentiation.
Species:  Mouse
Tissue:  Pancreas.
Technique:  Gene knockout.
References:  3
Mice with receptor knockout exhibit defects in tangential cortical interneuron migration.
Species:  Mouse
Tissue:  Brain.
Technique:  Gene knockout.
References:  21
Anterior-posterior guidance defects of monoaminergic projections. Mice with receptor knockout exhibit defects in anterior-posterior axon tract organisation in the brainstem.
Species:  Mouse
Tissue:  Full body, brainstem examined.
Technique:  Gene knockout.
References:  6
Mice with receptor knockout exhibit dysfunction of hippocampal connectivity and maturation and forebrain wiring. Defects in forebrain connections such as the anterior commissure and thalamocortical and corticospinal tracts.
Species:  Mouse
Tissue:  Several tissue/cell specific knockouts (Foxg1, Dlx5 promotor-driven); hippocampus, forebrain affected
Technique:  Gene knockout.
References:  5,22-23
Impaired axonal development. Celsr3 inactivation resulted in marked malformation in the forebrain, absence of anterior commissure, and abnormalities in major axonal tracts. Celsr3 inactivation did not alter neuronal maturation. The neural phenotype was similar to that caused by inactivation of Frizzled3.
Species:  Mouse
Tissue:  Full-body
Technique:  Gene targeting in embryonic stem cells.
References:  16
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Celsr3tm1Agof|Celsr3tm2Agof|Emx1+|Emx1tm1(cre)Krj Celsr3tm1Agof/Celsr3tm2Agof,Emx1tm1(cre)Krj/Emx1+
involves: 129P2/OlaHsd * 129S2/SvPas		 MGI:1858236  MGI:95387  MP:0008225 abnormal anterior commissure morphology PMID: 18487195 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0002961 abnormal axon guidance PMID: 15778712 
Celsr3tm1Agof|Celsr3tm2Agof|Foxg1+|Foxg1tm1(cre)Skm Celsr3tm1Agof/Celsr3tm2Agof,Foxg1tm1(cre)Skm/Foxg1+
involves: 129P2/OlaHsd		 MGI:1347464  MGI:1858236  MP:0008128 abnormal brain internal capsule morphology PMID: 18487195 
Celsr3tm1Agof|Celsr3tm2Agof|Emx1+|Emx1tm1(cre)Krj Celsr3tm1Agof/Celsr3tm2Agof,Emx1tm1(cre)Krj/Emx1+
involves: 129P2/OlaHsd * 129S2/SvPas		 MGI:1858236  MGI:95387  MP:0008128 abnormal brain internal capsule morphology PMID: 18487195 
Celsr3tm1Agof|Celsr3tm2Agof|Tg(mI56i-cre,EGFP)1Kc Celsr3tm1Agof/Celsr3tm2Agof,Tg(mI56i-cre,EGFP)1Kc/0
involves: 129P2/OlaHsd		 MGI:1858236  MGI:3609984  MP:0008128 abnormal brain internal capsule morphology PMID: 18487195 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0002152 abnormal brain morphology PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0000788 abnormal cerebral cortex morphology PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0000792 abnormal cortical marginal zone morphology PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0002878 abnormal corticospinal tract morphology PMID: 15778712 
Celsr3tm1Agof|Celsr3tm2Agof|Foxg1+|Foxg1tm1(cre)Skm Celsr3tm1Agof/Celsr3tm2Agof,Foxg1tm1(cre)Skm/Foxg1+
involves: 129P2/OlaHsd		 MGI:1347464  MGI:1858236  MP:0002878 abnormal corticospinal tract morphology PMID: 18487195 
Celsr3tm1Agof|Celsr3tm2Agof|Emx1+|Emx1tm1(cre)Krj Celsr3tm1Agof/Celsr3tm2Agof,Emx1tm1(cre)Krj/Emx1+
involves: 129P2/OlaHsd * 129S2/SvPas		 MGI:1858236  MGI:95387  MP:0002878 abnormal corticospinal tract morphology PMID: 18487195 
Celsr3tm1Agof|Celsr3tm2Agof|Tg(mI56i-cre,EGFP)1Kc Celsr3tm1Agof/Celsr3tm2Agof,Tg(mI56i-cre,EGFP)1Kc/0
involves: 129P2/OlaHsd		 MGI:1858236  MGI:3609984  MP:0002878 abnormal corticospinal tract morphology PMID: 18487195 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0003271 abnormal duodenum morphology PMID: 15778712 
Celsr3tm1Mrc Celsr3tm1Mrc/Celsr3tm1Mrc
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S6/SvEvTac * C57BL/6NCr)		 MGI:1858236  MP:0004274 abnormal embryonic/fetal subventricular zone morphology PMID: 19332558 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0004081 abnormal globus pallidus morphology PMID: 15778712 
Celsr3tm1Mrc Celsr3tm1Mrc/Celsr3tm1Mrc
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S6/SvEvTac * C57BL/6NCr)		 MGI:1858236  MP:0004081 abnormal globus pallidus morphology PMID: 19332558 
Celsr3tm1Mrc Celsr3tm1Mrc/Celsr3tm1Mrc
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S6/SvEvTac * C57BL/6NCr)		 MGI:1858236  MP:0002184 abnormal innervation PMID: 19332558 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0001175 abnormal lung morphology PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0000778 abnormal nervous system tract PMID: 15778712 
Celsr3tm1Mrc Celsr3tm1Mrc/Celsr3tm1Mrc
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S6/SvEvTac * C57BL/6NCr)		 MGI:1858236  MP:0006009 abnormal neuronal migration PMID: 19332558 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0002270 abnormal respiratory alveoli morphology PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0000470 abnormal stomach morphology PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0008227 absent anterior commissure PMID: 15778712 
Celsr3tm1Agof|Celsr3tm2Agof|Foxg1+|Foxg1tm1(cre)Skm Celsr3tm1Agof/Celsr3tm2Agof,Foxg1tm1(cre)Skm/Foxg1+
involves: 129P2/OlaHsd		 MGI:1347464  MGI:1858236  MP:0008227 absent anterior commissure PMID: 18487195 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0008129 absent brain internal capsule PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0001575 cyanosis PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0001405 impaired coordination PMID: 15778712 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0002058 neonatal lethality PMID: 15778712 
Celsr3tm1Mrc Celsr3tm1Mrc/Celsr3tm1Mrc
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S6/SvEvTac * C57BL/6NCr)		 MGI:1858236  MP:0002058 neonatal lethality PMID: 19332558 
Celsr3tm1Agof Celsr3tm1Agof/Celsr3tm1Agof
either: CD-1.129P2-Celsr3 or (involves: 129P2/OlaHsd * C57BL/6 * CD-1)		 MGI:1858236  MP:0001953 respiratory failure PMID: 15778712 
Biologically Significant Variant Comments
Well characterised amino acid changing SNPs include rs12107252 (R1758Q), rs3821875 (T805S), and rs3733085 (P157A).
General Comments
CELSR3 (adherin, EGF LAG seven-pass G-type receptor 3) is a receptor that belongs to Family IV Adhesion-GPCRs along with CELSR1 and CELSR2 [8]. The gene is localized on human chromosome 3 and mouse chromosome 9. Family IV Adhesion-GPCRs have orthologs in vertebrate and invertebrate species.

A recent publication reveals an increase in Celsr3 expression in pancreatic tumour stellate cells [4]. Activation of these cells or their trans-differentiation is regulated by paracrine and autocrine loops of growth factors which are associated with pathological conditions such as liver injury, cirrhosis as well as cancer.

References

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1. Beall SA, Boekelheide K, Johnson KJ. (2005) Hybrid GPCR/cadherin (Celsr) proteins in rat testis are expressed with cell type specificity and exhibit differential Sertoli cell-germ cell adhesion activity. J Androl, 26 (4): 529-38. [PMID:15955893]

2. Bjarnadóttir TK, Geirardsdóttir K, Ingemansson M, Mirza MA, Fredriksson R, Schiöth HB. (2007) Identification of novel splice variants of Adhesion G protein-coupled receptors. Gene, 387 (1-2): 38-48. [PMID:17056209]

3. Cortijo C, Gouzi M, Tissir F, Grapin-Botton A. (2012) Planar cell polarity controls pancreatic Beta cell differentiation and glucose homeostasis. Cell Rep, 2 (6): 1593-606. [PMID:23177622]

4. Erkan M, Weis N, Pan Z, Schwager C, Samkharadze T, Jiang X, Wirkner U, Giese NA, Ansorge W, Debus J, Huber PE, Friess H, Abdollahi A, Kleeff J. (2010) Organ-, inflammation- and cancer specific transcriptional fingerprints of pancreatic and hepatic stellate cells. Mol Cancer, 9: 88. [PMID:20416094]

5. Feng J, Xu Y, Wang M, Ruan Y, So KF, Tissir F, Goffinet A, Zhou L. (2012) A role for atypical cadherin Celsr3 in hippocampal maturation and connectivity. J Neurosci, 32 (40): 13729-43. [PMID:23035085]

6. Fenstermaker AG, Prasad AA, Bechara A, Adolfs Y, Tissir F, Goffinet A, Zou Y, Pasterkamp RJ. (2010) Wnt/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem. J Neurosci, 30 (47): 16053-64. [PMID:21106844]

7. Formstone CJ, Little PF. (2001) The flamingo-related mouse Celsr family (Celsr1-3) genes exhibit distinct patterns of expression during embryonic development. Mech Dev, 109: 91-94. [PMID:11677057]

8. Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB. (2003) There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini. Biochem Biophys Res Commun, 301 (3): 725-34. [PMID:12565841]

9. Lindenmaier LB, Parmentier N, Guo C, Tissir F, Wright KM. (2019) Dystroglycan is a scaffold for extracellular axon guidance decisions. Elife, 8. [PMID:30758284]

10. Nakayama M, Nakajima D, Nagase T, Nomura N, Seki N, Ohara O. (1998) Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening. Genomics, 51: 27-34. [PMID:9693030]

11. Qu Y, Glasco DM, Zhou L, Sawant A, Ravni A, Fritzsch B, Damrau C, Murdoch JN, Evans S, Pfaff SL, Formstone C, Goffinet AM, Chandrasekhar A, Tissir F. (2010) Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice. J Neurosci, 30 (28): 9392-401. [PMID:20631168]

12. Shima Y, Copeland NG, Gilbert DJ, Jenkins NA, Chisaka O, Takeichi M, Uemura T. (2002) Differential expression of the seven-pass transmembrane cadherin genes Celsr1-3 and distribution of the Celsr2 protein during mouse development. Dev Dyn, 223 (3): 321-32. [PMID:11891983]

13. Shima Y, Kawaguchi SY, Kosaka K, Nakayama M, Hoshino M, Nabeshima Y, Hirano T, Uemura T. (2007) Opposing roles in neurite growth control by two seven-pass transmembrane cadherins. Nat Neurosci, 10 (8): 963-9. [PMID:17618280]

14. Shima Y, Kengaku M, Hirano T, Takeichi M, Uemura T. (2004) Regulation of dendritic maintenance and growth by a mammalian 7-pass transmembrane cadherin. Dev Cell, 7 (2): 205-16. [PMID:15296717]

15. Thakar S, Wang L, Yu T, Ye M, Onishi K, Scott J, Qi J, Fernandes C, Han X, Yates 3rd JR et al.. (2017) Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. Proc Natl Acad Sci USA, 114 (4): E610-E618. [PMID:28057866]

16. Tissir F, Bar I, Jossin Y, De Backer O, Goffinet AM. (2005) Protocadherin Celsr3 is crucial in axonal tract development. Nat Neurosci, 8 (4): 451-7. [PMID:15778712]

17. Tissir F, De-Backer O, Goffinet AM, Lambert de Rouvroit C. (2002) Developmental expression profiles of Celsr (Flamingo) genes in the mouse. Mech Dev, 112 (1-2): 157-60. [PMID:11850187]

18. Tissir F, Goffinet AM. (2006) Expression of planar cell polarity genes during development of the mouse CNS. Eur J Neurosci, 23 (3): 597-607. [PMID:16487141]

19. Tissir F, Qu Y, Montcouquiol M, Zhou L, Komatsu K, Shi D, Fujimori T, Labeau J, Tyteca D, Courtoy P, Poumay Y, Uemura T, Goffinet AM. (2010) Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat Neurosci, 13 (6): 700-7. [PMID:20473291]

20. Wu Q, Maniatis T. (2000) Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes. Proc Natl Acad Sci USA, 97 (7): 3124-9. [PMID:10716726]

21. Ying G, Wu S, Hou R, Huang W, Capecchi MR, Wu Q. (2009) The protocadherin gene Celsr3 is required for interneuron migration in the mouse forebrain. Mol Cell Biol, 29 (11): 3045-61. [PMID:19332558]

22. Zhou L, Bar I, Achouri Y, Campbell K, De Backer O, Hebert JM, Jones K, Kessaris N, de Rouvroit CL, O'Leary D, Richardson WD, Goffinet AM, Tissir F. (2008) Early forebrain wiring: genetic dissection using conditional Celsr3 mutant mice. Science, 320 (5878): 946-9. [PMID:18487195]

23. Zhou L, Qu Y, Tissir F, Goffinet AM. (2009) Role of the atypical cadherin Celsr3 during development of the internal capsule. Cereb Cortex, 19 Suppl 1: i114-9. [PMID:19349379]

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