Understanding Celsrs Cadherin EGF LAG Sevenpass Gtype Receptors

Accepted Article Shandong 250012, China; Medicine, Jinan, Shandong 250012, China; DepartmentBiochemistry of and Molecular Biology, Shandong UniversitySchool of China Shandong, Jinan, Diseases, Degenerative Center, Augusta, GA 30912, USA College of Georgia Georgia, Reagents Un Shandong 250012,China; Affiliations: Affiliations: This article This protectedis by Allcopyright. rights reserved. cite this article as an 'Accepted Article', doi: 10.1111/jnc.12955 may whichlead version to differencesthis of between Version Please the and Record. beennot throughthe copyediting,typesetting, pagination and proofreading process This article hasbeen accepted for publicationand undergone fullpeer review but has 7 6 5 4 3 2 1 Xiao-Jing Wang receptors G-type seven-pass LAG EGF Cadherin - CELSRs Understanding Article Type: Review Wang Shandong University, School of Life Science, Jinan, Shandong, China; China; Shandong, Jinan, Science, Life of School University, Shandong Binzhou Medical University, Yantai, Shandong 264003, China; Jinan, Medicine, of School University Shandong Biology, Cell of Department and Education of Ministry the of Teratology Experimental Laboratory Key Shandong Provincial School Key laboratory for Protein Science of Chronic Chronic of Science Protein for laboratory Key School Provincial Shandong Medical andAnatomy Biology Cellular of Department Center, Biology Vascular Jinan, Medicine, of School University Shandong Physiology, of Department 1,5,7 , Lin-Lin Li 1,2,7# 1,2,7 , Dao-Lai Zhang , Dao-Lai , Xiao-Lin Han , Xiao-Lin 1,3,7# 1,5,7 , Zhi-Gang Xu , Zhi-Gang , Yuqing Huo , Yuqing iversityCharlie and Medical NorwoodVA

6 4 , Xiao Yu , Xiao , Ming-Liang Ma Ming-Liang , 5,7 *, Jin-Peng Sun Jin-Peng *, 1,7 , Wen-Bo , Wen-Bo 1,7 * Accepted Article This article This protectedis by Allcopyright. rights reserved. The # author) (corresponding Yu Xiao author: Corresponding * Abstract amino acids. the Mutationsecto-domain in or other gene locations ofCELSRs are ecto-domains thathomophilic form interactionsand encompass more than 2,000 development.All threemembers ofthe CELSR family (CELSR1-3) have large embryonic during polarity cell planar of control the and formation valve vessel differentiation, cell neuronal/endocrine as such processes biological many of regulators pivotal are which (GPCRs), receptors protein-coupled G adhesion of CELSR-targeted therapeuticreagents. new of design the for foundation the laying function, CELSR underlying prtools, asKO mice, such may conditional biochemical or biology cell advanced more with studies future motivation, this Given do mechanisms and the as regulatory do elusive, remain interactions homophilic beyond ligands endogenous of presence the and of CELSRs activationinactivation a limited and The oftissues. number dynamic in functions characterized few have but distributed broadly are they that considering properties of CELSRs, our knowledge of these receptors is still lacking, especially biochemical and functions the regarding made been has progress significant Although potential. therapeutic have may members CELSR of antagonists or agonists knockout (KO)animalshave many developmental defects. Therefore, specific humans. in diseases andother (NTDs) defects tube neural with associated Authors contributed equally to this work. work. this to equally contributed Authors cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup subgroup aspecial are (CELSRs) receptors G-type seven-pass LAG EGF cadherin

Email: [email protected] Email: author) (corresponding Sun Jin-Peng [email protected] Email: wnstream signaling these of receptors. ovide further insights into the mechanisms

Celsr

Accepted Article family are related to human diseases. receptor this within mutations genetic and development, during functions important family have cadherin repeats at their farN-termini. These proteins areinvolved in this of proteins because GPCRs adhesion of subgroup special a is receptor, G-type Piao 2007, Boutin physiological processes. (Paavola and other fertility male development, system neuronal for functions important have members,such GPCR adhesion that many al after cleavage after cleavage at (Lin their GPS subunits two into processed are GPCRs adhesion Many S3D). Fig. and and1B 1A (Fig. Fredriksson This article This protectedis by Allcopyright. rights reserved. (Arac domain (GAIN) autoproteolysis-inducing GPCR the of part is which (GPS), site proteolytic thatpotential encompasses mo adhesion largeN-terminal ecto-domainsuperfamily.a very theseof special Each has GPCRs Kahsai (Rosenbaum responses. cellular generates andultimately effectors downstream to couples turn in which stimuli, extracellular receiving upon change conformational a toundergo receptor 2013). All GPCRshave seven conserved transmembranehelices, enabling the largestprotein transmembrane superfamily(Chai extracellular environmentintracellular and group, activitya comprise and, the as the between exchange information the govern (GPCRs) receptors G protein-coupled Introduction Planar Cell Polarity (PCP). Development, CELSR, Adhesion, (GPCR), Receptor Protein-Coupled G words: Key . 2012). In recent years, cellular, physiological and genetic studieshave revealed The CELSR family, whosename deri is et al. etal. 2004). et al. The2011). adhesion GPCRs form uniquea subfamily within the GPCR et al. etal. 2003, Bjarnadottir 2012,Curtin 2012, Paavola &Hall 2012, Sun et al. 2009, Hanson Stevens& 2009, Shukla et al. et al. et al. et etal. 2004, Hsiao 2003, McGee Evolutionarily, CELSRs emerged early early emerged CELSRs Evolutionarily, 2011, Bae ved from cadherin EGF LAG seven-pass seven-pass LAG EGF cadherin from ved tifs/repeats and the conserved GPCR 2007, Hu as CELSRs, VLGR1/GPR98 and HE/GPR64, VLGR1/GPR98 CELSRs, as et al. et al. etal. et al. et al. et et al. et 2011, Hu 2014, Li 2014,Venkatakrishnan 2013)(Singer 2006, Davies 2014, Paavola Hall 2012)& etal. et al et al. et 2008, Jin . 2014,Arac etal. et al. et 2008, 2004, 2013, et al. et et al. et

Accepted Article receptor (Hadjantonakis Celsr1 CELSRs of Structure Gene and Cloning 1.The all ofwhich inform may research.future CELSR genetic association of pancreas neuronal, in CELSRs of functions known the CELSRs, of distribution tissue the CELSRs, of structures protein and gene the addressing CELSRs, of understanding current the discuss we mini-review, this of CELSRs thetheirat level molecular and mechanisms regulatory elusive. In remain roles the and distribution, broad their despite processes, physiological several only in functions known have CELSRs indeed, limited; is receptors these of knowledge Saade McVey respectivelyStanier (DoudneyAllache 2005, & (CVD), disease and cardiovascular (NTDs) defects tube neural with associated are Yates 2012b). Human genetic analysis alsohas shown that mutations in 2010, Qu et 2003, al. & Doudney human the of members three all for roles essential demonstrated Yates formation (FormstoneMason&et 2012,Nishimura2005, al. Tatin valve vessel during rearrangement cell in and development neuronal embryonic ( Nishimura (Usui contacts cell-cell and adhesion cell in CELSRs for roles important Langenhan 2013). al. et The initial characterizationthe of This article This protectedis by Allcopyright. rights reserved. counterpart, of the a compared withdiscovery mostand adhesion GPCRs, other CELSR1 et al. et al. etal. was first identified in mice as an orphan seven transmembrane domain domain transmembrane seven orphan an as mice in identified first was et al. , et al. CELSR2 et al. 2010a, Robinson 2010b, Wu 2011, Braun 2014,Arvind Flamingo 2010, Zhou 2012, Formstone 2010). Accordingly, recent studies have and CELSR3 CELSRs CELSRs

etal. (fmi) Stanier 2005, Devenport & Fuchs 2008,Ravni & Fuchs 2005,Stanier Devenport et al. et al. etal. et al. et , 2011, Feng etal.

) in vertebrate planar cell polarity (PCP) during during (PCP) polarity cell planar vertebrate ) in has facilitatedtheirgenetic study (Usui et al.1999, with diseases and potential CELSR signaling properties, properties, signaling CELSR potential and diseases with 1997). Because of its Because1997). larg 2012). Despite these progresses in CELSR research, our 2014, Samani 2009, Wada 2012, Adams 2012, et al. et and intraluminal valve formations, the intraluminal valve and etal. 2012a,Boutin al.2012,et Tissir et al. et etal. etal. 2006, Lewis 2008, Waterworth 2012,Harris2012, Juriloff & 2014, Talmud e size and low abundance, abundance, low size e and

functions of of functions et al. CELSR1 CELSR CELSR et al. et al. et Drosophila 2011,Feng et al. et etal. et al. et fmi 2013, Curtin family 2009, and revealed 2009, 1999, 2010, et al. et CELSR2 CELSR2

etal.

Accepted Article an N-terminal extracellular domain has CELSR1 full-length Human subfamilies. GPCR adhesion the to belong and domain extracellular alarge and region transmembrane hepta-helical a contain CELSRs All Structures Protein CELSR Deduced 2. spans 27 kb and is organized into 37exons (Fig. S1B and S1D). mouse and exons, 35 into organized 2000). Mouse resulted in the cloning of partial cDNAs from two other When length and encodes 3,579 putative amino acids. product of (stan) night Starry by characterized who researchtwo labs,named this ortholog This article This protectedis by Allcopyright. rights reserved. which encompasses 27kb and has 35 exons (Fig. S1A and S1C) (Formstone human from CHLC.GCT8C07), which spans 26 kb and is organized into 34exons, whereas 1998). Human and Celsr a exons S1C (Fig. and Two S1D). yearsafter the identification of Celsr1 in mice, and is organized intoexons; 35 the mouse these human using (FISH) hybridization situ in fluorescence by 22q13.3 chromosome to mapped human isolate only partialof cDNAs chromosome 15 (Fig. S1B). The mouse S1B). chromosome 15(Fig. Celsr1 mouse partial cloned The post-coitum. days at8.5 library cDNA embryonic mouse and an additional 878 bp in theuntranslated 3’ region were initially cloned froma Celsr3 ortholog from (mm CELSR3 CELSR3 , which were named MEGF2 and MEGF3, respectively (Nakayama respectively MEGF3, and MEGF2 named were , which Celsr1 fmi Celsr1 CELSR1 CELSR1 CELSR1 CELSR1 encodes 3,575 amino acids, and acids, amino 3,575 encodes Celsr2 CELSR2 is located on chromosome 3p21 (1.61cR from WI-7862, lod> 3), was identified, a search for proteins containing EGF-like domains domains EGF-like containing proteins for a search identified, was ) cDNA (ME2 clone) was used to map its gene location on mouse mouse on location gene its map to wasused clone) (ME2 ) cDNA (Usui Drosophila is located on chromosome 3 F3, which spans 25 kb and is is and kb 25 spans which F3, 3 chromosome on located is cosmid clones (Fig. S1A). The human Celsr1 was later mapped to human chromosome 1p21-.13 (3.05cR cosmid clones. The humancosmidThe clones. et al containing transmembrane domain 2 to the C-terminus C-terminus the to 2 domain transmembrane containing . 1999,Chae was independently cloned and functionally andfunctionally cloned was independently of 2,465 amino of 2,465 amino acids and seven a Celsr3 Celsr1 Celsr1 et al. Celsr1 is located on chromosome 9 F2, which which 9 F2, chromosome on located is ME2 cloneME2 was thenused to screen and 1999). The reportedtranslational stan stan gene spans 135 kb and has 37 CELSR1 (hsCELSR1) (hsCELSR1) CELSR1 mRNA is more than 12 kb in kb in 12 than more is mRNA Celsr CELSR1 CELSR1 family family members, Flamingo (fmi) Flamingo genekb spans 177 locus was et al. et al. and and Celsr2

Accepted Article a hormone receptor motif at (HormR) th is There cysteines. conserved eight has and length in acids amino 60 approximately is domain The EGF-Lam domains. G laminin and EGF-CA the follow CELSR3 in domains also potential calcium receivers. One EG (Hohenester structure fold roll jelly has a domain G laminin the and acids, amino 40 approximately has domain EGF-CA Each S2). and 1A, 1B (Fig. G domains laminin two by separated (EGF-CA) domains been investigated indetail (Shima yet not has cis/trans-dimerization and calcium-regulated resolved, been not have interaction-mediating CELSR2/3 signaling, the structures of CELSRs cadherin repeats trans-cadherin potential despite However, interaction. cadherin calcium-regulated Therefore, cadherin repeat structures provide alikely structural mechanism for calcium. without cell) same the within molecules between (interactions cis-dimers 2002, Takeichi trans-dimer formation (between cells) of two individual cadherin pairs (Shima pairs cadherin individual two of cells) (between formation trans-dimer clump aggregation of cadherin-expressing cells, andrecent FRET results have shown Tissir (Georgieva coordination calcium require repeats cadherin successive (Overduin domains constant immunoglobulin to similar is and strands beta seven of composed 2010, Allache This article This protectedis by Allcopyright. rights reserved. (Caddy solved previously been have fragments and ecto-domains cadherin (Takeichi 1990, Shapiro& Weis 2009). The crystal structures of several classical DXNDNAPXFare motifs responsible and for ex or DRE, DXD, signature have which domains), (EC) cadherin extracellular called The N-terminal end of containsCELSRs nine cadherin repeats (110 residues, also hormone receptor motif (HormR) close to the 1A,(Fig. GPS 1B). and one domains, (LAG) G two laminin domains, (EGF)-like factor growth epidermal six repeats, cadherin atypical nine contains CELSR1 of N-terminus the receptor, G-type seven-pass LAG EGF a As cadherin terminus. C its at domain transmembrane After the nine cadherin repeats in CELSRs, there are five calcium-binding EGF EGF calcium-binding five are there CELSRs, in repeats cadherin nine the After et al. et et al. et 2002a). Early experiments showed that calcium promotes the tissue-like tissue-like the promotes calcium that showed experiments Early 2002a). et al et al. 1996, Overduin . . 2012). In these structures,the cadherin repeat monomer is 1981, Zhang etal. etal. et al. et etal. 1995) (Fig. S3A). Connectionsbetween 2009). By contrast, cadherins formweak may 20) 2007). F-Lam domain in CELSR1/2 and two EGF-Lam EGF-Lam two and CELSR1/2 domain in F-Lam e e C-terminus of these repeats (Arac 1999) (Fig. S3B). Both of domainsthese are rclua acu idn Fg A B 1B) 1A, (Fig. binding calcium tracellular et al. et 2003, et al. et et al. etal.

Accepted Article broken by C-A mutations have been reported to decrease ligand binding and and binding ligand decrease to reported been have mutations C-A by broken (Venkatakrishnan change conformational or binding ligand efficient for CELSRs of structure extracellular the stabilize hsCELSR2; and C2602 and C2674 from hsCELSR3) can forma disulfide bond to extracellular loop (C2531 andC2603 from hsCELSR1; C2439 and C2511 from second and loop 1A, extracellular (Fig. first the region from pair Cys helical Aconserved 2B). and 1B transmembrane seven a is there CELSRs, of GPS the After experimentation. additional requires contexts physiological in proteases by regulated or auto-proteolysis through subunits different into is replaced hsCELSR3 Rin by (Fig. 2A). Therefore, whether hsCELSRs are separated H base general the and hsCELSR3, G in and hsCELSR1 A in by replaced is nucleophile CELSR2 has the general base H2355 and nucleophile T2357, whereasthe conserved 2004, Hsiao (Lin proteolysis during base general a as serves H aconserved and nucleophile a as functions T/S/C conserved a which in mechanism, hydrolysis cis-auto vitro, several adhesion GPCRs areprocesse The GAIN domains of CELSRs follow their regionsHormR 1A(Fig. and 1B and InS3D). requires further investigation.. and unknown is interaction ligand/hormone in participates CELSRs of HormR such asthe GLP-1 receptor (Underwood essential element for peptide and hormone interactions with B1/Secretin-like GPCRs, 2002b).However, N-terminal an alladhesion GPCRHormRs lack Drosophila This article This protectedis by Allcopyright. rights reserved. ligand binding domain (Paavola & Hall 2012, Arac occasionally regarded is potential family and observed adhesion the asa GPCR in often is HormR domains, adhesion N-terminal the to addition In cysteines. conserved 2012) (Fig. 1A and S3C). The HormR has two conserved tryptophans and several

CELSR homolog CELSR et al. 2011,Hu fmi et al results in a loss of receptor function (Tissir function receptor of loss a in results . 2014,Arac et al. et et al et d into two fragments at their GPS via a a via GPS their at two fragments d into et al 2010, Runge . 2013) . (Fig. 2B). Disulfide bonds . 2012). Interestingly, only human et al . 2012). HormR deletion HormR 2012). the. in etal. 2008). Whether the α -helix, which is an et al. et al.

Accepted Article expression thein epithelium and nervous systems ofboth embryos and imaginal the of characterization original The tissues (Usui 3. occurs mechanism CELSRs with binding partners (Huber partners binding its from dissociation following exposed is region PEST the once degradation undergo may regulatemay receptor turnover in the (Meyercell enriched Ser and Pro. Moreover, each CELSR severalhas predicted PESTregions that its of because motifs binding SH3 and sites phosphorylation potential multiple contains CELSR1 of region The cytoplasmic Asp. and Glu as such residues, acidic and C-tail containing 532amino acids. All CELSR C-termini areenriched with Ser, Thr, Pro have 304andacids, 305amino respectively, in their C-termini,hsCELSR3 has a longer hsCELSRS2 and hsCELSR1 Whereas lengths. tail cytoplasmic different have CELSRs helix, seventh the After 2B). (Fig. receptor the for flexibility structural provide which C-tail.third Theintracellular CELSRs contains loopof approximately 20 aminoacids, downstream effectors inthe and cytoplasm intracellularincludes loops 1-3 and the trans-membrane region,the intracellularpart CELSRs serves of as dockinga point for 2007, Rosenbaum (Lefkowitz changes conformational such during functions This article This protectedis by Allcopyright. rights reserved. and W2576 inhsCELSR2; P2689 and W2738 in hsCELSR3), corresponding toP211 including the conservedP2618 in and TM5 W2668 in the TM6 hsCELSR1of (P2526 cytoplasmic region ofthe CELSR by co key lock model of CELSR, in whichthe extracellular signal istransduced theto Afterthe extracellular region, the seven transmembrane helix is thehub thein 2001) inactivate GPCRs, such as the gonadotropin-releasing hormone receptor (Gross and the toggle switch W286 switch toggle the and expressed in many tissues (Table 1 and Fig. S4). During development, During S4). Fig. 1 and (Table tissues in many expressed

iseDsrbto Distribution Tissue et al. et etal. 1999) 2007, Rasmussen et al. . In mammals, In 6.48 2001, Singh of the of requires furtherinvestigation. Celsr Drosophila nformational change. Several residues, Several nformationalchange. β Celsr 2-adrenergic receptor, may have important important have may receptor, 2-adrenergic et al. etal. 1 , Celsr 2007) (Fig. 2B). Next theto 2006). Whetherregulatory similar 2006). a etal. 2 and counterpart 2011). Cadherins reportedly Celsr3 Celsr3 et al. 2008, Cherezov are ubiquitously ubiquitously are fmi identified its its identified Celsr1-3 Celsr1-3 etal. et al. et 5.50

Accepted Article Zhang Zhang systems (Fig. S4B-S4D) (Formstone reproductive and digestive the as well as and spleen, kidney, heart, lungs, skin, life change in dynamic (Lewis retina inner the in circuitry pathway visual that shown also have theRecent olfactory bulb. rostral andcentral studiesregionsmigratory the of stream the gyrus, dentate the of hilus the layer, granular cerebellar the in present still is postnatal development. Although development. postnatal The expression of which has been observed bothin NSC and post-mitotic neural cells (Boutin al expressedpost-mitotic inprimarily neural layer ofdentatelayer gyrus in adultthe brain (Boutin zones during brain development, telencephalic ependymal zones and the subgranular confined to areas ofneuralstem cell(NSC patternsofmRNA expression brain.expression the different The in the eye (Shima (Shima (Shima members are expressed inthe brain and spinal cord (Tissir al. post-natal development until the adult stage (Formstone germ cells, whereas This article This protectedis by Allcopyright. rights reserved. complementa The functions. expression is regulated spatially and temporally, suggesting that they have distinct post-natal down-regulation of of down-regulation post-natal Little 2001,Little Shima interestingin feature . 2012). The pattern of 1997, Tissir

Celsr1-3 Celsr1-3 et al et al . 2011).. expression is also observed in other non-neural systems, such as the the as such systems, non-neural other in observed also is expression . 2002, Curtin is broadly expressed inthe nervoussystem et al et al Celsr1 etal.

In the rodent testis, testis, rodent the In Celsr1/3 . 2002,Devenport &Fuchs 2008, TissirGoffinet & 2006). All three . 2002) (Fig. S4).Duringdevelopment, Celsr1 Celsr1 different developmentalsystems.(Tissir Celsr3 2002). Celsr2 is etal. and expression, reduced by reduced is expressed during normal development of the ON ON the of development normal during expressed is ry patternof Celsr1 Celsr2 2003, Montcouquiol expression overlaps with thatof

Celsr3 et al and are expressed in Sertoli cells, with persistent persistent with cells, Sertoli in expressed are decreasing the number of NSCs of NSCs number the decreasing Celsr3 . 2000, Shima Celsr2 expression is downregulated postnatally, it it postnatally, downregulated is expression Celsr1 Celsr2 ) proliferation, including the ventricular ventricular the including proliferation, ) cells butnotinneural stemcells (Boutin is expressed exclusively in post-mitotic in post-mitotic exclusively expressed is expression remains stable throughout throughout stable remains expression et al in adults (Fig. S4C) (Beall and et al. . 2012). By contrast, Celsr3 Celsr3 etal. et al 2011). In contrast withthe etal.

from embryonic embryonic from earlyand 2008), pigmentand cellsof . 2002, Yates et al Celsr Celsr expression is expression etal. 2000, Hadjantonakis . 2002b), cochlea Celsr1 members exhibit 2002, Formstone & Celsr1 Celsr1 and et al during early early during an an Celsr3 Celsr3 et al. et al. et is primarily is Celsr3 . 2010, 2005, 2012). is et , et Accepted Article phenocopied by by phenocopied caudally to r6.The dysfunction in FBM migration of the in mutations four of identification the to led which zebrafish, in FBM migration in alterations for screen (che (N-ethyl-N-nitrosourea anENU by The importance ofCELSRs facial in branch to addition in growth axon guidance, and dendrite migration, neuronal of regulators critical as been characterized have CELSRs (1) wild-type counterparts, the FBM neurons in c in neurons FBM the counterparts, wild-type 4. (Hadjantonakis process proteolytic uncharacterized at act the through by but fragment an may GPS auto-cleavage not isproduced CELSR1 This antibody. CELSR1-specific the by detected been have (p85) fragment al. as thewell floor as roofplates and of 2001), Little & (Formstone skin embryonic of cells epidermal the and cells germ hair specific CELSR2/3 antibodies. CELSR1 protein expression has been demonstrated in S4A) expressed in whiskers; however, (Tatin S4D) formationintraluminal valve (Fig. during rearrangements cell directing and junctions adherens regulating in vessels Fuchs 2008). CELSR1 and the PCPprotein VANGL2 were also important lymphatic in (Ravni S4D) (Fig. proteins PCP other with interacting by (Fig. S4C).(Cortijo insulin-producing reduces pancreas This article This protectedis by Allcopyright. rights reserved. Johnson

1998). Interestingly, both full-length CELSR1 (p400) and a cleaved CELSR1

At the protein level, only CELSR1 has been characterized because of a lack of of proteinbeenAtlacklevel, thecharacterizedbecause has a CELSR1 only of h hsooia cin fCLR ntenrossse The physiological actions of CELSRs in the nervous system The Physiological Actions of CELSRs

et al. 2000). 2000). The loss of Celsr2 et al. et celsr2 Dgen/Dgen 2012). CELSR1 participates in thedevelopment of skinhair / off road off mutant The mice. conditional inactivationof Celsr2 Celsr3 β locus (Wada locus (Wada -cell differentiation-cell fromendocrine progenitors the hindbrain and spinal cord (Hadjantonakis cord spinal and hindbrain the and mical formula: C3H7N3O2)) mutagenesis mical C3H7N3O2)) formula: transcripts are not detected in whiskers (Fig. (Fig. whiskers in detected not are transcripts

vertebrate PCP and neuronal tube closure. closure. tube neuronal and PCP vertebrate iomotormigratio (FBM) Celsr3 et al. elsr2 function in the developing developing the in function et al mutants are unablemigrate mutants are to 2013). Both celsr2 et al . 2006). Comparedwiththeir etal. . 1998). zebrafish mutants is zebrafish 2009,Devenport & Celsr2 n was first revealedwas n and Celsr1 Celsr2 are in et Accepted Article inactivation of inactivation of inactivation conditional the although contrast, By migration. neuron FBM regulates mutant mice, indicating that specific CELSR2 signaling inside the FBMdirectly cells of in the brainstem (Tissir al. et 2005, Fenstermaker et al.2010). Regional inactivation defects guidance anterior-posterior and tracts axonal of development the in defects Celsr3 growth, dendrite in role inhibitory its to addition In length. dendrite decreases than opposing manner (Shima et al. 2007). By contrast, 2004). al. et (Shima length neuron pyramidal cortical adecreased and neurons Purkinje of trees dendritic simplified RNAi-mediated mammals, In 2012). Boutin al. et growth from homologous neuroblasts of the opposite hemisegmentet (Gao al. 2000, 2012). Flamingo mutant flies exhibit impaired reciprocal inhibition of dendritic al. et (Boutin guidance axon and development dendrite in roles important play control the ability of FBM cells to migrate (Qu migration during development. Whereas 2014). These results suggestthat of phenocopies are which mice, mutant This article This protectedis by Allcopyright. rights reserved. of phenotype the of exacerbation an exhibit mice double-mutant under FBM neurons interneurons (Formstone Mason& 2005). Moreover, calbindin-positive of movement radial the and interneurons caltetinin-positive migrate, to neurons (Qu the direction of FBM neuron migration, migration, neuron FBM of direction the Celsr1 Celsr3 In addition to their key functions in FBM cell migration, migration, cell FBM in functions key their to addition In et al is essential foraxon guidance. . 2010). Although with with further demonstrates the requirement for functional for requirement the demonstrates further Isl1-Cre Celsr1 Celsr3 Isl1-Cre in progenitors by does not cause apparent migrational dysfunction, the specific specific the dysfunction, migrational apparent cause not does Celsr3 is an important player in the tangential of player in the movement is important an causes a phenotypethatsimilar of causes a to deficiency does not impair the ability of FBM of ability the impair not does deficiency Celsr1-3 Celsr3 Celsr3 Celsr3 Nk6.2-Cre Celsr2 Fzd3 Celsr1 are coordinated to regulate FBM neuron neuron FBM regulate to coordinated are mutant mice exhibit multi-faceted multi-faceted exhibit mice mutant knockdownwithRNAi increases rather mutant mice(Qu et al. 2010, Qu etal and - Celsr3 has an important function in guiding guiding in function important an has Celsr2 causes abnormal rostralmigration 00. . 2010). 3 may operate may together to regulates neurite growth in an an in growth neurite regulates Celsr3 knockdown results in Celsr2 ko/ko Celsr3 Celsr3 and and and and Celsr2 Celsr2 Celsr2 in axonal Celsr3 Dgen/Dgen Dgen/Dgen Dgen/Dgen Dgen/Dgen also et al.

Accepted Article heterozygous heterozygous two identified have researchers suspension, tail during spinning and curling belly behavior, head-shaking exhibit that mice identify to experiments mutagenesis asymmetry and somitogenesis (Formstone Mason & 2005). By using ENU in roles additional and closure tube neural in role conserved a to play shown signal, which is coordinated by by coordinated is which signal, have suggestedthattwo distinct PCP signals operate in brain ciliated cells. The first data published recently Moreover, cells. neuroepithelial of convergence midline promotes and manner planar-polarized in a contraction actomyosin-dependent for essential is activity kinase Rho Up-regulated (Nishimura 3) (Fig. activity kinase Rho increase to PDZ-RhoGEF and DAAM1 Dishevelled, with coordinating by plate neural the of bending (Lei bifida spina vertebrate PCP and neuronal tube closure. A chick A chick closure. tube neuronal and PCP vertebrate that and neurons Purkinje the of complexity the and membrane in vitro. Two novel membrane invitro. Two the plasma to trafficking protein CELSR1 to affect shown been have mutations fao udneadpasipratrlsi ri iig importantbrainwiring. roles plays in of axonguidance and that demonstrate ehrinA-EphAforward signaling together, Taken 2014). (Chaiet al. resultsthe defects called craniorachischisis (CRN) (Robinson tube neural severe the have that fetuses human in identified then were mutations This article This protectedis by Allcopyright. rights reserved. In the peripheralnervous system, 2008). al. et (Zhou targets sub-cerebral and commissure anterior the to projections several defects in neural tube closure that lead to perinatal lethality. Six Six lethality. perinatal to lead that closure tube neural in defects several PCP (Curtin orientation of the sensory hair cells of the cochlea, which typicalis a phenotype of A detailed mechanistic study suggested that CELSR1 regulates the polarized polarized the regulates CELSR1 that suggested study mechanistic A detailed Accumulating evidence has also demonstrated that that demonstrated also has evidence Accumulating et al celsr1 celsr1 et al. . 2003).. Both homozygous Celsr2 mutants ( mutants 21) 2014). is important in the dendrite length in pyramidal neurons neurons pyramidal in length dendrite the in is important celsr1 Celsr1 Celsr 2/3, Fzd3 Fzd3 2/3, Celsr Celsr3 crsh mutations were also recently associated mutations with and -deficient axons failto respond to celsr1 celsr1 the simultaneous apicalconstriction and and crsh Sc et al γ Vangl2, Celsr1/fmi-1 Celsr1/fmi-1 ) that have defects in the the in defects thathave ) and Celsr3 Celsr3 . 2012). All of these 2012). All of . celsr1 Celsr1 organizes the single-cell single-cell the organizes is essential in many steps Sc et al is a regulator isa key of γ ortholog, mice displayed displayed mice . 2012). . 2012). Celsr1 c-fmi1 Celsr1

, was , was

Accepted Article results suggest that Celsr2 and Celsr3 might have redundant functions in pancreas pancreas in functions redundant have might and Celsr3 Celsr2 that suggest results (Boutin Vangl2 anisomycin increases pancreatic agonist JNK the and phosphorylation, c-JUN substrate JNK reduced in results cells) is observed after E14.5 (Cortijo et al. 2012). The loss of both Celsr2 and -3 KO mice. TheKO mice. capacity to clear glucose was decreased in This article This protectedis by Allcopyright. rights reserved. crossing inhibiting specifically because pancreas the in function its rather but system nervous the in function of celsr3 (Cortijo hybridization situ in using E14.5 at epithelium pancreatic the of cells endocrine and cells exocrine progenitors, the in bud three E11.5, all pancreatic at the detected and in homeostasis glucose of roles essential The (2). 2014) theprosencephalon using mechanisms other than classical epithelial PCP(Qu et al. suggested that by governed is which signal, second the cells; individual of polarity glucagon ( glucagon at E14.5. In Celsr2/Celsr3 decrease in dramatic DKOmice, produce a cells that pancreatic adult islet and compared with compared and with Celsr3

KO mice led to reduced insulin-containing insulin-containing reduced to led mice KO During pancreas development, mRNA transcripts of of transcripts mRNA development, pancreas During Celsr2 mRNA is significantly increased in the pancreatic buds of Celsr3 KO mice mice KO Celsr3 of buds pancreatic the in increased significantly is mRNA Celsr2 euae iseplrt nbt ailpoeiosadeedmlcls cells ependymal and progenitors radial both in polarity tissue , regulates et al. et Celsr3 pancreatic in α β β cells), insulin ( cells (Cortijo cell development and appropriate glycemic control. control. glycemic appropriate and development cell 2014). Using conditional Celsr2 Celsr2 flox/flox flox/flox Celsr3 mice with Celsr3 and β cell differentiation from progenitor cells is not due to its to its due not is cells progenitor from differentiation cell et al Celsr3 Celsr3 flox/flox Celsr2 β expression in epithelial pancreas progenitor cells by by cells progenitor pancreas epithelial in expression cells), ghrelin, polypeptide (pp cells) and somatostatin ( somatostatin and cells) (pp polypeptide ghrelin, cells), . 2012). Therefore, Pdx1-cre mice, was accompanied by decreased numbers of of numbers decreased by accompanied was mice, and and β function redundantly to redundantly function -cell differentiationCelsr3 in KO mice. These Celsr3 Celsr2 etal. mice reproduced the phenotype of of phenotype the reproduced mice in pancreas inpancreas and 2012). A constitutive 2012). A lossof β -3 Celsr3 cells after E14.5. The essential role mutants, another recent study study recent another mutants, CELSRs is an essential gene in gene essential an is β Celsr3 Celsr3

regulate axonal guidance in axonalguidance regulate cell differentiation and and differentiation cell Celsr1 were broadly expressed expressed broadly were flox/flox and and

Celsr1 /Pdx1-cre Celsr3 , Fzd3 Celsr3 are Celsr3 mice , and in

Accepted Article Harris 2012, Doudney &Stanier 2005). Among theidentified mutations of nervous system diseasesbirthat (Allache central severe most the of one (NTDs), defects tube neural the in mutations rare (Curtin models animal different using studies by closure tube neural of process the in gene essential an as characterized been has CELSR1 PCP, vertebrate of regulator key the As 2). (Table tumors and disease heart coronary system, nervous the in defects tube the in mutations humans, In 5. vessels. lymphatic in formation valve intraluminal during of role essential the demonstrate results (Tatin junctions adherens the of maturation the and VE-cadherin of stabilization the by regulating rearrangement cell endothelial lymphatic during valves. Further mechanistic studies have suggested that This article This protectedis by Allcopyright. rights reserved. (3). pathways. JNK regulating by differentiation cell endocrine promote and development valves. Bycontrast, Celsr1 micro-domains cell at membrane plasma to discrete filopodia the from recruited are VANGL2 protein E18.5 (Tatin at leaflets valve and at E17.5 directions flow the with intersecting cells endothelial PCP protein CELSR1 is induced around Prox1 around induced is CELSR1 protein PCP precise regulation at multiple levels. Along with valve initiation,the expression of and polarity undergoand rearrangementto

ahlgclAto nRlto oDsae Pathological Actionin Relation to Diseases Celsr1

In developing lymphatic valves, endothelial cells profoundly change their shape shape their change profoundly cells endothelial valves, lymphatic developing In flox/flox

et al function in theintraluminal valve formationlymphatic of vessels :Prox1-Cre . 2003).Consistently,. multiple et al . 2013). During cell rearrangement, both CELSR1 and its interacting Celsr2 -cell contacts. Both Both contacts. -cell ERT2 embryos exhibit abnormal organization in their lymphatic lymphatic their in organization abnormal exhibit embryos -/- and and CELSR1-3 Celsr3 genes cause many diseases, such as neural neural as such diseases, many cause genes flox/flox Celsr1 Celsr1 et al CELSR1 :Prox1-Cre form intraluminal leaflets that require high . 2012, Robinson indirecting cell rearrangements cell clusters atE16.5and then in Crsh mutations have been identified as as been identified have mutations mutant mice and miceand mutant ERT2 Celsr1 Celsr1 embryos have normal normal have embryos plays a pivotal role role pivotal a plays et al et al . . 2012, Juriloff & . 2013). These. CELSR1

Accepted Article carcinomas (Ammerpohl methylationthe of DNA Aberrant 2). (Table tumors different in observed been also have CELSRs PCP, of investigation. further andawaits described well relevance of 2011, Kathiresan Chow (Virtanen (T2DM) mellitus diabetes 2 type in disease cardiovascular levels, CAD reducedLDL-c associated with and 2010). Othernon-coding genetic variants in an intergenic region betweenthe corona and levels LDL circulating with of regions untranslated 3’ the at mutation A genetic kinase-regulated signals arepotentially impaired thisin special mutant. that indicating CELSR1, of site phosphorylation PKC potential a is which C-terminal cytoplasmic tails. The S2963-T2966 del mutation hasdeleted a SSR motif, S2964L, P2937L, R2949Q and S2963-T2966 del) have been observed in the This article This protectedis by Allcopyright. rights reserved. al disease (CVD) (Qi 4) (Allache laminin EGF-like anddomain the GPS; and R2438Q close to the GPS (Table 2 and Fig. S2190L, A2228V, N2230S, R2312P,A2339T, P2352S, and R2359Cbetween the last G1628R, S1726G, and R1835C inthe laminin G-like domain;A2075V, R2121C, D1889N, and P1976T in the EGF-like domain; D1401G, T1443P, R1456Q, R1526W, protocadherin repeats; V1244I after the protocadherin repeats; D1365N, R1886H, R541W, V551M, Q757R,A773V, Q834X, R836C, G934R and V1008L in the NTDs, associated with occur 30 mutations . 2008, Samani The PCP pathway also plays vital roles in carcinogenesis. As the core components Non-coding genetic mutations of of mutations genetic Non-coding PSRC1 etal. genes (rs646776 and rs599839 in the CELSR2-PSRC1-SORT1 locus) are et al 2012, Samani CELSR2 . 2012, Robinson 2012,. et al. et al etal. CELSR1 CELSR1 in lipid metabolism and cardiovascular disease has not been been not has disease cardiovascular and metabolism inlipid . 2008, Nakayama 2007, Kathiresan 2011, Waterworth 2011, et al. et al gene CpG loci has been identified in hepatocellular hepatocellular in identified been has loci CpG gene 2012),the and downregulation of . 2007,. Sandhu et al CELSR2 . 2012).. Five ry arteryry disease (CAD) (Waterworth et al. et al et al and MIrisk in and Hispanic individuals in the extracellular domain, including including domain, extracellular the in are associated with cardiovascular are associated with cardiovascular . 2009).. However, the functional 2008, Nakayama et al. et . 2010, Jeemon . CELSR1 CELSR1 2008, Arvind CELSR2 mutations (N2739T, (N2739T, mutations (rs660240) is associated etal. et al. et al CELSR1 CELSR1 et al. 2011, Samani 2011, 2009) (Table2). 2009) . 2014,. Qi has been been has 2012, et al CELSR2 et al . et .

Accepted Article In mammals, In mammals, Diego (dgo), and probably other, less clearly identified, members (Boutin al.2012).et receptors transmembrane seven the including proteins, PCP key with interact functionally In the fruit fly,the human 6. PotentialSignaling tumor and stages is required. polarized bending of the neural plate (Fig. 3) (Nishimura (Nishimura 3) (Fig. plate neural the of bending polarized the during PDZ-RhoGEF and DAAM1 Disheveled, through activity kinase Rho regulate (Boutin 3) (Fig. -2 and Vangl1 of evaluation Further stages. particular at development, activate or inactivate inactivate or activate efficient in vitro research tools, such selectiveas compoundsthat specifically of lack the is cause potential One detail. in studied been not have inactivation (Shima of (Cortijo development pancreatic and different roles of regulatory spatial temporal and chronic lymphocytic leukemia patients (Kaucka PRICKLE1 contrast, both both contrast, This article This protectedis by Allcopyright. rights reserved. directions Future identified in cases ofnon-nodal mantle cell lymphoma (Del Giudice functional roles of The S4). Fig. and 1 (Table tissues other and heart, lungs, skin, the in and systems The three Celsr2/3 - 3 may regulate the JNK pathway and the phosphorylation status of c-Jun during during c-Jun of status phosphorylation the and pathway JNK the regulate 3 may et al , Frizzled CELSRs CELSRs FRIZZLED3/7 increases intracellular calcium through a PLC activity-dependent pathway pathway activity-dependent PLC a through calcium intracellular increases . . 2007). However,the signaling events triggered by Celsr CELSRs CELSRs CELSR1 , tetraspanin Van Gogh (vang), Dishevelled (dsh), Prickle (pk), and and (pk), Prickle (dsh), Dishevelled (vang), Gogh Van , tetraspanin are broadly expressed in neuronal, digestive and reproductive and reproductive digestive neuronal, in expressed broadly are works together with Frizzled3and -6, Dishevelled1 and -2and CELSRs CELSRs Celsr

may bemay correlated with progressionthe ofspecific tumor types and several other PCP pathway components, such as as such components, pathway PCP other several and and have been extensively studied in neuronal systems by by systems neuronal in studied extensively been have CELSR CELSR members. DISHEVELLED2/3 et al orthologs et al . 2012). Downstream 2012). . CELSR1 ofCELSRs, may . 2012). Duringneurite growth, the activation CELSR fmi , are up-regulated in B lymphocytes of of B lymphocytes in up-regulated , are and et al. members in different tumor types types tumor different in members CELSR stan 2013). Consideringthe specific have been found to to been have found members during embryonic embryonic during members et al . 2012), whereas CELSRs et al. activation or or activation 2012). 2012). In VANGL2 Celsr 2 , Accepted Article CELSRs CELSRs of roles explicit the studies, animal recent these following appreciated been has This article This protectedis by Allcopyright. rights reserved. (Zhou defects axonal severe present and birth after of homozygotes example, For models. KO specific using Although the functional importance of of importance functional the Although that could induce unwanted signaling cascades. Direct evidence and mapping of the the of andmapping evidence Direct cascades. signaling unwanted induce could that interactions cis-homophilic non-specific excluding trans-interactions, specific form to intact remain and fold should region interaction ecto-domain CELSR homophilic the case, that In cell. neighboring a from CELSR the for ligand be the may cell one from (Shima growth neurite during functions opposite the exhibit but binding homophilic selective through signaling CELSRs. Previous studies have suggestedthat CELSR2and CELSR3 elicit downstream for ligands artificial or natural either as demonstrated clearly been have ligands small explicit no however, interactions; protein or ligands multiple for platform a provide 2014, Zhang & Xie 2012,Wang transduce the signals inside the cells to initiate intracellular responses (Chai et al. transmembranegroupthat of proteinsextracellular sense information and the largest of consists which superfamily, (GPCR) receptor transmembrane seven elucidated by combining these 2010). The elucidation of specific roles foreach & Fuchs 2008, Curtin Celsr1 The homozygotes of mice also exhibited abnormal FBM neuron migration (Qu (Qu migration neuron FBM abnormal exhibited also mice Tatin (Cortijo characterized recently been have formation valve intraluminal of roles functional the mice, interact extensivelythe with nervous system. By using specific or activity neuronal by controlled are development tissue and functions most of defects severe the by blocked is system neuronal the et al KO mice are embryonic lethal with defects in neural tube closure (Devenport (Devenport closure tube neural in defects with lethal embryonic are mice KO at theat molecular cellularand levels re . 2013). In the future, specific Celsr et al Crsh . 2003, Yates. Celsr2/3 and et al etal. Celsr Celsr . 2007). Therefore, 2007). CELSR. a ecto-domain the of flox/flox 2014). CELSRs 2014). have large ecto-domains that in pancreatic development and development pancreatic in Sc et al γ Celsr mutants and 20% of the homozygotes of mc ihtsu-pcfcCemc. with mice tissue-specific Cre mice. CELSRs . 2010b, Ravni. roles in different tissues/organs may be be may tissues/organs different in roles aneuie CELSRs belong to the main elusive. Celsr during tissue-level development development tissue-level during et al member in tissues other than member other tissues than in Celsr3 CELSRs . 2008, Tissir et al et al . 2010, Tissir. KO just KO mice perish . 2009). Celsr KO mice because because KOmice conditional KO KO conditional Celsr1 et al Celsr2 et al . 2005).. et al in . 2012, KO . Accepted Article This article This protectedis by Allcopyright. rights reserved. (Singer their domain GAIN in aGPS contain which all subfamily), GPCR LNB7TM (or subfamily GPCR adhesion the to belong CELSRs CELSRs. of ligands natural the define to undertaken be should molecules adhesion with other interactions CELSR potential and interactions homophilic CELSR of examination biochemical molecules, most ofwhich also contain multiple EGF or cadherin repeats.Adetailed adhesion other with interact CELSRs that possibility the exclude not does CELSRs ligand for otherCELSRs. The homophilic interaction of the large ecto-domain of to confirm required are interface specific GPS cleavage (Paavola & Hall 2012, Hall Paavola & (Paavola cleavage GPS following regions N-terminal their removing after activity constitutive their enhance et al with typical Gq-coupled GPCRs. Therefore, further studies are required to to required are studies further Therefore, GPCRs. Gq-coupled typical with than slower much is increase calcium intracellular CELSR2-CR-/CELSR3-CR-induced the However, coupling. Gq through signal may 2/3 CELSR that indicated specifically blocked by the PLC inhibitor U73122 (Shima CELSR3-CR) significantly increased the concentration of intracellular calcium, which is and (CELSR2-CR repeats cadherin recombinant CELSR applying growth, neurite or Frizzledstudythe functional a In Hall 2012). on (Paavola & roleof asSmoothened such pathway, signaling Gprotein non-classical through or LEC1, and GPR56 including GPCRs, adhesion other as such proteins, G through signaling elicit CELSRs whether not clear is it However, c-Jun. of status phosphorylation the control andCELS CELSR2 that and cells the inside regulate Rho CELSR1 activity kinase may that have revealed Previous studies certain physiological or pathological contexts. in fragments different into separated be could CELSRs that possibility the not exclude cells (Shima et al. 2007, Lin 2004, etal. Sun etal.2013). However, this finding does wereuncleaved studies, CELSR3 and CELSR2 . 2013).. Several GPCRs, including GPR56, BAI1 and VLGR1, haveshown been to R3 may interfere with the JNK pathway and and pathway JNK the with interfere may R3 that that ecto-domain one CELSRof the is the et al theirafter exogenous transfection in . 2011,. Hu et al et al . 2013,Arac et al . 2007). These. results . . In2014). recent Celsr2/3 et al . 2012, Sun in Accepted Article This article This protectedis by Allcopyright. rights reserved. of Distribution 1. Table Research in Team University (IRT13028). (JQ201320 to X.Yu) and theprogram for Changjiang Scholars Innovativeand Scholars Young Distinguished for Fund Science Natural Shandong the X.Yu), Interdiscipline Fund of ShandongUniversity (2012JC021 to ZG. Xu. and 2014JC029 to NationalFo Natural Huo); Science YQ. Program of China (2013CB967700 to X.Yu and ZG. Xu; 2012CB910402 to SunJP. and (81200951 to ofChina Foundation Science Acknowledgements: cascades ofCELSRs. signaling downstream explicit and coupling G protein the specific characterize Celsr1 Classification

Brain, cord,spinal eye knhi Skin hair Spleen Lung Kidney stomach the and Esophagus Cochlea This work was supported by grants from the National Natural Natural National the from grants by supported was work This Celsr1-3 Tissue in tissues

undation of China undation ofChina (31271505 to Sun), JP. XJ. Wang); NationalXJ. Wang); Key ResearchBasic (Ravni (Formstone (Yates (Formstone (Curtin (Shima (Montcouquiol (Formstone Reference (Zhang (Shima (Shima (Hadjantonakis et al et al et al. et al et et al et al et al

. 2010b). . 2009). . 2002) . 2002) . 2002) . 2003) et al et al et al 21) 2011) et al. et al . 2000). 00 2000) . 2000). . 1997) 2008) Accepted Article This article This protectedis by Allcopyright. rights reserved. Celsr3 Celsr2

Pancreas retina Inner Testis Cochlea Brain, cord,spinal eye Pancreas Testis Heart Spleen Lung Hair follicles andglands serous Whiskers stomach the and Esophagus Cochlea Brain, cord,spinal eye vessels Lymphatic (Cortijo (Lewis (Beall (Shima (Formstone (Formstone (Shima (Shima (Shima (Shima (Formstone (Cortijo (Beall (Formstone (Formstone (Hadjantonakis (Hadjantonakis (Tatin (Devenport & Fuchs 2008) et al. et et al et al et al et al et et al et al et al et al et al et al . 2005) 03 2013) . 2005) . 2011) . 2002) . 2002) . 2002) . 2002) . 2002) et al et al et al et al et al . 2012). . 2012). et al et al 00 2000) . 00 2000) . 2000). . 2000). 2000). . 1997) . 1997) Accepted Article This article This protectedis by Allcopyright. rights reserved. Table 2. CELSR2 CELSR1 Classification Classification

CELSR1-3 Cardivasocular disease leukemia lymphocytic Chronic lymphoma cell Mantle carcinoma Hepatocellular Neural tube defects

addfeetdsae diseases different and Diseases

(Waterworth (Nakayama (Nakayama ( (Nishimura (Juriloff & Harris 2012) Stanier(Doudney & 2005) (Robinson (Allache (Jeemon (Qi (Del Giudice Giudice (Del (Ammerpohl (Chow (Virtanen (Kaucka (Samani (Samani Kathiresan et al et al . 2011). et al et al et al et al et al Reference et al . 2012) et al et al et al et al 03 2013) . . 2012) . 2007) et al 01 . 2011) et al . 2012) . 2012)

. 2012) 2012) . . 2009) . 2008 . 2012) ., 2012) . 2010)

)

Accepted Article This article This protectedis by Allcopyright. rights reserved. and J. A. Cox, J., J. Carr, C., M. Ng, D., C. Langefeld, B. I., Freedman, M., L. Raffield, N., J. Adams, Allache, R., De Marco, P., Merello, E., Capra, V. and Kibar, Z. (2012) planarE., the (2012) Role and Capra, Z. De of Allache, R., Kibar, cellpolarityV. Merello, P., Marco, Ammerpohl, O., Pratschke, J., Schafmayer, C. et et C. Schafmayer, J., Pratschke, O., Ammerpohl, Arac, D., Boucard, A. A., Bolliger, M. F., Nguyen, J., Soltis, S. M., Sudhof, T. C. and Brunger, A. T. (2012) (2012) T. A. Brunger, and C. T. Sudhof, M., S. Soltis, J., Nguyen, F., M. Bolliger, A.A., Boucard, D., Arac, Bjarnadottir, T. K., Fredriksson, R. and Schioth, H. B. (2007) The adhesion GPCRs: a unique family ofG family a unique GPCRs: adhesion The H. B. (2007) R.andSchioth, T. Fredriksson, K., Bjarnadottir, Beall, S. A., Boekelheide, K.and Johnson, K. J. (2005) Hybrid GPCR/cadherin (Celsr) proteins in rat Arvind, P.,Nair, J., Jambunathan, S., Kakkar, V.and V. Shanker, J.(2014) CELSR2-PSRC1-SORT1 gene Bae, B. I., Tietjen, I., Atabay, K. D. et al. (2014) etal. D. K. Atabay, I., Tietjen, I., B. Bae, Boutin, C., Goffinet, A. M. and Tissir, F. (2012) Celsr1-3 and brain Tissir, inPCP Celsr1-3 cadherins and development. A.M. F.(2012) Boutin, C.,Goffinet, Braun, T. R., L. al. F.,Been, Singhal, lipidgenes ofA replication A.etGWAS-derived in study (2012) Boutin, C., Labedan, P., Dimidschstein, J.et al. (2014) A dual role for planar cell polarity genes in Caddy, J., Wilanowski, T., Darido, C. et al. (2010) Epidermal wound Caddy,Wilanowski,repair C.et regulated T., al.wound is Darido, J., Epidermal the planar by (2010) the Diabetes Heart Study. Study. Heart Diabetes the Bowden, D. W. (2014) Analysis of common and coding variants with cardiovascular disease in 94, gene CELSR1 in neural tube defects and caudalagenesis. cirrhotic liver and hepatocellular carcinoma. carcinoma. and hepatocellular liver cirrhotic EMBO J, EMBO autoproteolysis. mediates GPCRs cell-adhesion domain of conserved evolutionarily A novel Mol LifeSci, tissues. and peripheral central inboth roles withimportant receptors protein-coupled activity. adhesion cell cell-germ Sertoli and with cell are exhibitdifferential typetestis specificity expressed patterning. cortical cerebral regional regulates Indian cohort. plasma an lipidlevels and in artery disease Asian coronary andwith expression association Top DevBiol, PLoS One, PLoS 11q23.3 region thechromosomal Indians: Asian ciliated cells. cell polarity signaling pathway. cell polarity signaling pathway. 176-181.

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Sequence alignment the transmembraneof regions the of CELSR proteinsfrom adhesion GPCRs. Sequence alignment the GPSof for CELSR1-3 proteins and several other humans, mice and miceand humans, Drosophila n; orange, EGF-CA domain; EGF-CA orange, n; . magenta, LamG domain; domain; magenta, LamG

Accepted Article This article This protectedis by Allcopyright. rights reserved.