- Research article
- Open Access
Expression profile of the entire family of AdhesionG protein-coupled receptors in mouse and rat
BMC Neuroscience volume 9, Article number: 43 (2008)
The Adhesion G protein-coupled receptors (GPCRs) are membrane-bound receptors with long N termini. This family has 33 members in humans. Several Adhesion GPCRs are known to have important physiological functions in CNS development and immune system response mediated by large cell surface ligands. However, the majority of Adhesion GPCRs are still poorly studied orphans with unknown functions.
In this study we performed the extensive tissue localization analysis of the entire Adhesion GPCR family in rat and mouse. By applying the quantitative real-time PCR technique we have produced comparable expression profile for each of the members in the Adhesion family. The results are compared with literature data and data from the Allen Brain Atlas project. Our results suggest that the majority of the Adhesion GPCRs are either expressed in the CNS or ubiquitously. In addition the Adhesion GPCRs from the same phylogenetic group have either predominant CNS or peripheral expression, although each of their expression profile is unique.
Our findings indicate that many of Adhesion GPCRs are expressed, and most probably, have function in CNS. The related Adhesion GPCRs are well conserved in their structure and interestingly have considerable overlap in their expression profiles, suggesting similarities among the physiological roles for members within many of the phylogenetically related clusters.
G protein-coupled receptors (GPCRs) can be divided into five subfamilies according to the GRAFS classification system: Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin . The Adhesion GPCRs, also known as long N-terminal seven transmembrane receptors related to family B (LNB-TM7) and epidermal growth factor seven transmembrane (EGF-TM7) receptors. This family is the second largest GPCR family with 33 members in humans and 30 members in mice and rats. The endogenous ligands are discovered for BAI1, GPR56, CD97 and EMR2, while the rest of the Adhesion GPCRs remain orphans.
The Adhesion receptors are characterized by long N-termini with complex domain architecture including GPCR proteolytic site (GPS), epidermal growth factor, thrombospondin, pentraxin, immunoglobulin, olfactomedin, cadherin domains . Several of the domains in the N-termini have been shown to have cell adhesion functions and to be responsible for cell-to-cell and cell-to-matrix interactions [3, 4]. The GPS domain is thought to be an intracellular cleavage motif, which is crucial for transport of the receptor from ER to the membrane . The Adhesion GPCRs are cleaved into two parts: N-terminal and 7TM part with the C-terminal. Nevertheless it has been reported that the N-terminal is responsible for ligand binding and is able to re-associate with the rest of the receptor and in this way initiate intracellular signalling cascade . The genes coding for Adhesion GPCRs are difficult to study due to their complex genomic structure and a large number of exons.
The Adhesion GPCRs can be divided into seven groups according to phylogenetic analysis (Figure 1) . The brain angiogenesis inhibitors (BAIs) 1–3 form group I and are known to be mainly expressed in the brain. The N-terminal of BAI receptors contains GPS, hormone binding domain and thrombospondin repeats which are likely to be involved in the angiogenesis inhibitor function of BAIs. The role of BAIs in tumor suppression has been closely investigated as angiogenesis is an essential part of tumor formation . BAI1 has been recently reported as a receptor for phospatidylserine involved in recognition and internalization of apoptotic cells . GPR56 (group II) is another Adhesion GPCR with a role in tumor development . Mutations in GPR56 have also been reported to cause human brain malformations . It is described that GPR56 is able to build complex with cell-surface protein tetraspanin CD81 and Gαq/11 and is able to bind tissue transglutaminase, TG2 [11, 12].
GPR64 also called HE6 (group II), unlike GPR56, has its only known function in the periphery and disruption of this gene results in mouse male infertility . The very large G-protein-coupled receptor (VLGR1) is important for normal development of auditory hair bundles in the inner ear . The functions of other five members of group II are not known.
The Adhesion receptors forming group III can be divided into two groups according to the architecture of their N-termini. EMR1, EMR2, EMR3, EMR4, CD97 and ETL receptors have all a variable number of epidermal growth factor (EGF) and calcium binding domains and are reported to be important components of the immune system . EMR2 and EMR3 are missing in the mouse and rat genomes. CD55 and chondroitin sulphate have been described as ligands for CD97, while chondroitin sulphate is also a ligand for EMR2. It is also suggested that EGF domains in the N-termini of CD97 are essential for CD55 binding. [15, 16]. LEC1, LEC2 and LEC3 on the other hand are proposed to play more central roles like synaptic cell adhesion  and have a different repertoire of domains in the N-termini (hormone binding, olfactomedin and galactose binding lectin domains). LEC2 has been reported to bind α-latrotoxin from black widow spider venom .
GPR123, GPR124 and GPR125 belong to group IV of Adhesion GPCRs. GPR123 has been reported to have specific expression in the brain . GPR125 was recently presented as a stem cell marker with a possible therapeutic use . Both these receptors have protein-protein interaction domains in the form of leucine rich repeats, while GPR124 and GPR125 have immunoglobulin domains in N-termini as well.
CELSR1–3 receptors (group V) have the most complex domain structure with cadherin repeats, two types of EGF domains, laminin G and hormone binding domains. CELSR receptors are thought to have crucial functions in CNS development. Mutations in CELSR1 cause abnormal neural tube development in mice . CELSR2 and CELSR3 seem to have opposite effects in neurite growth regulation; CELSR2 is enhancing neurite growth while CELSR3 is suppressing it. . Unlike CELSR receptors, the members of group VI, GPR133 and GPR144 as well as group VII, GPR110, GPR111, GPR113, GPR115 and GPR116 do not have any discovered function.
The majority of Adhesion GPCRs are poorly studied, with specific expression patterns and physiological functions yet to be discovered. Until today, the published expression data on many Adhesion GPCR members is limited to a few tissues and is performed by different methods with varying sensitivity. Therefore, an overall expression analysis of Adhesion GPCRs is useful for comparison of expression and identifying specific patterns. It is also an important step towards finding the functions of the poorly studied receptors.
In this study we report an extensive tissue localization analysis of the entire Adhesion GPCR family in rat and mouse. By applying the quantitative real-time PCR technique we have produced comparable expression patterns for each Adhesion family member. We have compared expression patterns between rat and mouse and recent in situ hybridization data for mouse from the large Allen Brain Atlas project  as well as human and mouse ESTs . We describe similarities in Adhesion GPCR expression patterns between rat and mouse as well as within groups of Adhesion GPCRs.
The mouse Adhesion GPCR gene sequences were downloaded from GenBank (Additional File 2) and 7TM regions were identified with Conserved Domain Database . The tree calculations were carried out using ClustalW alignment of TM regions, which was bootstrapped 100 times and distances were calculated with PROML from Phylip 3.67 package. The Maximum-Likelihood consensus tree is presented in Figure 1.
We performed an expression analysis of 30 rat and mouse Adhesion GPCR family members in a range of central and peripheral tissues. Seven coronal sections of rat brain (Additional file 1), a number of brain regions and peripheral tissues were isolated from mice and rats and used for RNA isolation and cDNA synthesis. The expression values of four housekeeping genes were used to calculate normalization factors for mouse and rat cDNA. Relative expression values displayed as a fold increase from the detected minimum expression for rat and mouse Adhesion GPCRs are presented in Figures 2, 3, 4, 5, 6, 7. Expression of BAI1 and BAI2 from group I was detected only in brain regions of rat and mouse. BAI3 transcripts were detected mostly in brain, with very low levels in some peripheral tissues (Figure 2). The expression data of BAI receptors is in agreement with previously published results [25, 26]. GPR56, GPR64, GPR126 and VLGR1 from group II were detected in central and peripheral tissues, whereas GPR97, GPR112, GPR114 and GPR128 were detected in peripheral tissues (Figures 2, 3 and 6). The members of group III LEC1, LEC2, LEC3 and ETL were expressed ubiquitously in both rat and mouse, whereas LEC2 and LEC3 had higher levels in CNS compared to levels in the periphery (Figure 4). The members of group III CD97, EMR1 and EMR4 were detected mostly in peripheral tissues and at very low levels in the brain (Figures 4, 5). The expression profile of receptors from Adhesion group III is in agreement with previous reports [27–31]. The member of group IV GPR123 displayed central expression, while the other members GPR124 and GPR125 showed ubiquitous expression (Figure 5). The members of group V CELSR2 and CELSR3 were detected mainly in CNS, while CELSR1 was found both in central and peripheral tissues (Figure 6). These results confirmed previously published expression data of CELSR receptors [32, 33]. Group VI member GPR133 was detected in both CNS and periphery (Figure 6). GPR144, which is a pseudogene in rat, was not detected in any of the examined mouse tissues (results not shown). Group VII members GPR110, GPR111, GPR113 and GPR115 were detected in only few peripheral tissues (Figure 7). GPR116 was detected in all analyzed tissues, except blood, but mainly at low levels (Figure 7).
In this paper we present for the first time the expression chart of 30 members of Adhesion GPCRs in mouse and rat. Together with EST data from human and mouse  and previously published Allen Brain Atlas in situ hybridization data  this provides the most comprehensive information about the expression pattern of the Adhesion family of GPCRs (Figures 1, 2, 3, 4, 5, 6, 7).
Adhesion receptors is an evolutionary conserved group, for example an Adhesion like genes have been described in fruit fly (Drosophila melanogaster)  and in the choanoflagellate (Monosiga brevicollis) . According to our phylogenetic analysis based on TM regions of Adhesion receptors they formed seven groups (Figure 1), which is in agreement with previously published studies . Despite that phylogeny was based only on TM regions the N-termini of the receptors in each group had similar domain types and organization. Surprisingly, our results showed that the members within each group also share considerable similarities in their expression profiles (Figure 1). So according to our results group I with BAI1, BAI2, BAI3; group IV with GPR123, GPR124, GPR125; group V with CELSR1, CELSR2, CELSR3 and even LEC1–3 and ETL1 which form a cluster within group III showed predominant expression in the brain of rat and mouse (Figures 2, 4, 5 and 6).
The Adhesion GPCR group containing GPR123, GPR124 and GPR125 is one of the least studied groups. The detailed CNS profile of GPR123 was recently published by Lagerström et al. with some indications of important neuronal functions . It is therefore very exciting that our results display wide expression in the rat and mouse brain for all 3 members of this group. In contrast to GPR123, which displayed specific central expression, GPR124 and GPR125 displayed also very wide peripheral expression (Figure 5). It is very interesting that both the human and mouse ESTs for GPR125 are detected in stem cells and it was recently reported that GPR125 could be used therapeutically as a stem cell marker for generation of vessels . The N-terminals of GPR124 and GPR125 contain GPS, leucine-rich repeats, Ig domain and hormone binding domain in contrast to GPR123, which is lacking all of these domains. It is therefore tempting to speculate about if any of these domains have a role in peripheral actions of GPR124 and GPR125. Other proteins with leucine-rich repeats like LINGO-1 and LRRK2 have been shown to play a role in structural and functional integrity of neurons involved in Parkinson's disease . The members of this group are present in teleosts , amphioxus and fruit fly (unpublished data). As this group is present within most species with a nervous system and have a wide CNS expression, members from this family could have their main function within the CNS.
Similarly to the centrally expressed Adhesion GPCR genes, the genes expressed predominantly in peripheral tissues are also found in phylogenetic clusters. High levels of GPR128 transcripts were detected in stomach, and all parts of intestine. This is in agreement with the observation that the highest number of ESTs for GPR128 from human and mouse are found in the gastrointestinal (GI) tract (Figure 3). The GPR128 is unlikely to play a role in immune system regulation as it is not detected in high levels in immune system specific organs. The GI specific expression profile of GPR128 could possibly indicate a function in cell migration during development of GI tract endothelium. Two other genes from group II, GPR97 and GPR114, were also expressed in the GI tract but they were also detected at high levels in thymus, spleen and blood (Figure 3). In addition, the highest number of ESTs for these genes was detected in immune cells, spleen and bone marrow. Altogether this indicates that GPR97 and GPR114 most probably are involved in functions of immune system in humans and rodents.
GPR56, GPR64 and GPR126 from Adhesion GPCR group II displayed ubiquitous expression (Figures 2, 3). GPR56 is most studied of these receptors. It is reported to play a role in development of human cerebral cortex  as well as tumor development . According to our results, the expression of GPR56 is highest in mouse pancreas and rat kidney. GPR64 has been described to regulate the function of the male reproductive system . Our results together with data from Allen Brain Atlas  display expression of GPR64 in hypothalamus, brain stem, substantia nigra and spinal cord. This was surprising to us as several publications have described GPR64 as an epididymal specific receptor. Therefore it is likely that GPR64 could also have an additional function in CNS.
Mutations in VLGR1 are known to cause audiogenic seizures in mice . Hence VLGR1 expression in embryonic CNS is widely described not only in mammals but also in other vertebrates like zebrafish . Interestingly, our results indicate that there are common expression sites of VLGR1 in zebrafish embryo and adult rat such as hypothalamus and eye (Figure 6). Such similarity in expression patterns between mammals and teleosts points at remarkable conservation of function of the VLGR1 receptor during vertebrate evolution.
GPR133 and GPR144 are relatively recently discovered  and poorly studied Adhesion GPCRs. The presence of GPR133 like sequence (XM_001197663) in purple sea urchin (Strongylocentrotus purpuratus) indicates a long evolutionary history and an important physiological function. The expression of GPR133 was highest in intestine, skin, adipose tissue and olfactory bulb (Figure 6), which points toward a function in periphery. The inability to detect GPR144 transcripts in mouse tissues verifies that GPR144 is a murine pseudogene.
GPR116 is the only member of the Adhesion GPCR group VII with ubiquitous expression (Figure 7). The expression profile of GPR116 with highest transcript levels in lung, olfactory bulb and heart is most similar to the ETL and CD97 receptors. This could be a sign of functional similarities between these receptors. GPR110, GPR111 and GPR115 have common expression site in the rat eye. Two of these receptors, GPR111 and GPR115 also share expression in the rat skin. These receptors have similar structure in their N-termini and similar protein length. It is possible that these receptors play a role in similar peripheral functions like epithelial cell adhesion in eye epithelium and skin.
It is remarkable that phylogenetic clusters of Adhesion GPCRs seem to have either predominant central or peripheral expression in rat and mouse tissues. Though, it is also clear that within the phylogenetic clusters the expression profiles are not identical as Adhesion GPCRs are expressed in a large number of tissues. If we analyze the functions of the well studied Adhesion GPCRs, it is evident that even if the receptors from the same phylogenetic cluster do play roles in similar physiological processes, they do not have the same function and sometimes can even have opposite functions. One possible explanation for this is that Adhesion receptors are very well conserved during evolution and sub-functionalization was a common process among phylogenetic clusters of Adhesion GPCRs. Adhesion receptors participate in highly complex processes like development of nervous system and immune system response. These processes require often a strict sequence of steps with different types of adhesion molecules participating at the different stages. Altogether the Adhesion GPCRs are a unique and fascinating family of membrane receptors with conserved evolutionary history and a number of vital physiological functions.
Animal handling and tissue isolation
A number of adult male and female 129sv mice and Sprague-Dawley rats (Scanbur, BK AB) were kept in separate air-conditioned rooms (12 h dark/light cycle) at 22–23°C in an air humidity of 55%. The animals had free access to water and food pellets (Labfor, Lactamin, Sweden). These conditions were maintained for 7 days, and at the end of the period the animals were sacrificed by decapitation (rats) or cervical dislocation (mice) between 3 and 6 hours into the light period. All animal procedures were approved by the Uppsala Ethics Committee and followed the guidelines of European Communities Council Directive (86/609/EEC). Different brain regions and peripheral tissues were isolated. With regard to the rat brains, they were taken out immediately after decapitation. Two whole rat brains were sliced into coronal cross sections (approximately 3 mm thick) using a rat brain matrix (Pelco International, Canada) as presented in Fig. 1. The remaining rat brains were dissected in more detail. The entire hypothalamus was carefully removed by lifting it from the brain with a slightly curved forceps. Thereafter the following regions were manually dissected with the guidance of a rat brain atlas (Paxinos G., Watson C., 1997. The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego, CA): prefrontal cortex, motor cortex and hippocampus. The first section (approximately bregma 5.20–4.20 mm) was denoted prefrontal cortex. Motor cortex was collected from sections approximately between bregma 4.20–2.70 mm and included primary and secondary motor cortex. The hippocampus was collected from several sections and therefore comprised the hippocampus CA1–3 and the dentate gyrus. The tissues were immersed into RNA-later solution (Ambion, USA), kept at room temperature for 1 hour and thereafter stored at -80°C until further processed.
RNA isolation and cDNA synthesis
Individual tissue samples were homogenized by sonication in TRIzol reagent (Invitrogen, Sweden) using a Branson sonifier. Chloroform was added to the homogenate, which was then centrifuged at 10 000 g at 4°C for 15 minutes. The water phase was collected and RNA was precipitated with isopropanol. The pellets were washed with 75% ethanol, air dried and dissolved in RNAse free water. DNA contamination was removed by treatment with DNAse I (Roche Diagnostics, Sweden) at 37°C for 4 h where after the DNAse I was inactivated by heating the samples to 75°C for 15 minutes. Absence of DNA contamination in the RNA was confirmed by PCR and RNA concentration was determined using a Nanodrop® ND-1000 Spectrophotometer (NanoDrop Technologies, Delaware, USA). cDNA was synthesized with M-MLV reverse transcriptase (Invitrogen, Sweden) using random hexamers as primers according to the manufacturers' instructions. The quality of the cDNA was confirmed by PCR.
Primer design and evaluation
Sequences for rat and mouse house keeping genes and all known Adhesion GPCR gene sequences were downloaded from GenBank. GenBank accession numbers are presented in Additional File 2. All primers were designed with Beacon Designer v4.0 (Premier Biosoft, USA) and positioned within TM regions of the Adhesion GPCRs. The primers sequences for rat and mouse Adhesion GPCRs and house keeping genes are displayed in Additional File 2.
Quantitative Real-Time PCR
The cDNA was analyzed in quantitative real-time PCR with a MyiQ thermal cycler (Bio-Rad Laboratories, Sweden). Each real-time PCR reaction with a total volume of 20 μl contained cDNA synthesized from 25 ng of total RNA; 0.25 μM of each primer, 20 mM Tris/HCl (pH 8.4), 50 mM KCl, 4 mM MgCl2, 0.2 mM dNTP, SYBR Green (1:50 000). Real-time PCR was performed with 0.02 u/μl Taq DNA polymerase (Invitrogen, Sweden) under the following conditions: initial denaturation at 95°C for 4 min, followed by 50 cycles at 95°C for 15 s, 55–62°C for 30 s (optimal annealing temperature) and 72°C for 30 s. This was followed by 84 cycles at 55°C for 10 s (increased by 0.5°C per cycle). All real-time PCR experiments were performed in duplicate. A negative control for each primer pair and a positive control with 25 ng of rat and mouse genomic DNA, respectively, was included on each plate.
Data analysis and relative expression calculations
MyiQ software v 1.04 (Bio-Rad Laboratories, Sweden) was used to analyse real-time PCR data and derive threshold cycle (Ct) values. Melting curves were analysed to confirm that only one product was amplified and that it was different from the negative control. LinRegPCR  was used to calculate PCR efficiencies for each sample. After that Grubbs' test (GraphPad, USA) was applied to exclude the outliers and calculate average PCR efficiency for each primer pair. The delta Ct method  was used to transform Ct values into relative quantities with standard deviations and the highest expression was normalized to 1. The GeNorm software  was used with results from four housekeeping genes in order to calculate normalization factors for every tissue to compensate for differences in cDNA amount. Thereafter the normalized quantities were calculated and minimum expression was set to 1. All relative expression values were displayed as fold increase from the detected minimum expression.
Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB: The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003, 63 (6): 1256-1272. 10.1124/mol.63.6.1256.
Bjarnadottir TK, Fredriksson R, Schioth HB: The adhesion GPCRs: a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues. Cell Mol Life Sci. 2007, 64 (16): 2104-2119. 10.1007/s00018-007-7067-1.
Krasnoperov V, Bittner MA, Holz RW, Chepurny O, Petrenko AG: Structural requirements for alpha-latrotoxin binding and alpha-latrotoxin-stimulated secretion. A study with calcium-independent receptor of alpha-latrotoxin (CIRL) deletion mutants. J Biol Chem. 1999, 274 (6): 3590-3596. 10.1074/jbc.274.6.3590.
Obermann H, Samalecos A, Osterhoff C, Schroder B, Heller R, Kirchhoff C: HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia. Molecular reproduction and development. 2003, 64 (1): 13-26. 10.1002/mrd.10220.
Krasnoperov V, Lu Y, Buryanovsky L, Neubert TA, Ichtchenko K, Petrenko AG: Post-translational proteolytic processing of the calcium-independent receptor of alpha-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. J Biol Chem. 2002, 277 (48): 46518-46526. 10.1074/jbc.M206415200.
Volynski KE, Silva JP, Lelianova VG, Atiqur Rahman M, Hopkins C, Ushkaryov YA: Latrophilin fragments behave as independent proteins that associate and signal on binding of LTX(N4C). The EMBO journal. 2004, 23 (22): 4423-4433. 10.1038/sj.emboj.7600443.
Kudo S, Konda R, Obara W, Kudo D, Tani K, Nakamura Y, Fujioka T: Inhibition of tumor growth through suppression of angiogenesis by brain-specific angiogenesis inhibitor 1 gene transfer in murine renal cell carcinoma. Oncology reports. 2007, 18 (4): 785-791.
Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS: BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature. 2007, 450 (7168): 430-434. 10.1038/nature06329.
Ke N, Sundaram R, Liu G, Chionis J, Fan W, Rogers C, Awad T, Grifman M, Yu D, Wong-Staal F, Li QX: Orphan G protein-coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway. Molecular cancer therapeutics. 2007, 6 (6): 1840-1850. 10.1158/1535-7163.MCT-07-0066.
Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, Straussberg R, Dobyns WB, Qasrawi B, Winter RM, Innes AM, Voit T, Ross ME, Michaud JL, Descarie JC, Barkovich AJ, Walsh CA: G protein-coupled receptor-dependent development of human frontal cortex. Science. 2004, 303 (5666): 2033-2036. 10.1126/science.1092780.
Little KD, Hemler ME, Stipp CS: Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association. Molecular biology of the cell. 2004, 15 (5): 2375-2387. 10.1091/mbc.E03-12-0886.
Xu L, Begum S, Hearn JD, Hynes RO: GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2006, 103 (24): 9023-9028. 10.1073/pnas.0602681103.
Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U: Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Molecular and cellular biology. 2004, 24 (19): 8642-8648. 10.1128/MCB.24.19.8642-8648.2004.
McGee J, Goodyear RJ, McMillan DR, Stauffer EA, Holt JR, Locke KG, Birch DG, Legan PK, White PC, Walsh EJ, Richardson GP: The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles. J Neurosci. 2006, 26 (24): 6543-6553. 10.1523/JNEUROSCI.0693-06.2006.
Hamann J, Stortelers C, Kiss-Toth E, Vogel B, Eichler W, van Lier RA: Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97. European journal of immunology. 1998, 28 (5): 1701-1707. 10.1002/(SICI)1521-4141(199805)28:05<1701::AID-IMMU1701>3.0.CO;2-2.
Stacey M, Chang GW, Davies JQ, Kwakkenbos MJ, Sanderson RD, Hamann J, Gordon S, Lin HH: The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans. Blood. 2003, 102 (8): 2916-2924. 10.1182/blood-2002-11-3540.
Sudhof TC: alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins. Annu Rev Neurosci. 2001, 24: 933-962. 10.1146/annurev.neuro.24.1.933.
Lagerstrom MC, Rabe N, Haitina T, Kalnina I, Hellstrom AR, Klovins J, Kullander K, Schioth HB: The evolutionary history and tissue mapping of GPR123: specific CNS expression pattern predominantly in thalamic nuclei and regions containing large pyramidal cells. J Neurochem. 2007, 100 (4): 1129-1142. 10.1111/j.1471-4159.2006.04281.x.
Seandel M, James D, Shmelkov SV, Falciatori I, Kim J, Chavala S, Scherr DS, Zhang F, Torres R, Gale NW, Yancopoulos GD, Murphy A, Valenzuela DM, Hobbs RM, Pandolfi PP, Rafii S: Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature. 2007, 449 (7160): 346-350. 10.1038/nature06129.
Curtin JA, Quint E, Tsipouri V, Arkell RM, Cattanach B, Copp AJ, Henderson DJ, Spurr N, Stanier P, Fisher EM, Nolan PM, Steel KP, Brown SD, Gray IC, Murdoch JN: Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr Biol. 2003, 13 (13): 1129-1133. 10.1016/S0960-9822(03)00374-9.
Shima Y, Kawaguchi SY, Kosaka K, Nakayama M, Hoshino M, Nabeshima Y, Hirano T, Uemura T: Opposing roles in neurite growth control by two seven-pass transmembrane cadherins. Nature neuroscience. 2007, 10 (8): 963-969. 10.1038/nn1933.
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR: Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007, 445 (7124): 168-176. 10.1038/nature05453.
Boguski MS, Lowe TM, Tolstoshev CM: dbEST--database for "expressed sequence tags". Nat Genet. 1993, 4 (4): 332-333. 10.1038/ng0893-332.
Marchler-Bauer A, Panchenko AR, Shoemaker BA, Thiessen PA, Geer LY, Bryant SH: CDD: a database of conserved domain alignments with links to domain three-dimensional structure. Nucleic Acids Res. 2002, 30 (1): 281-283. 10.1093/nar/30.1.281.
Nishimori H, Shiratsuchi T, Urano T, Kimura Y, Kiyono K, Tatsumi K, Yoshida S, Ono M, Kuwano M, Nakamura Y, Tokino T: A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene. 1997, 15 (18): 2145-2150. 10.1038/sj.onc.1201542.
Shiratsuchi T, Nishimori H, Ichise H, Nakamura Y, Tokino T: Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenetics and cell genetics. 1997, 79 (1-2): 103-108.
Sugita S, Ichtchenko K, Khvotchev M, Sudhof TC: alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J Biol Chem. 1998, 273 (49): 32715-32724. 10.1074/jbc.273.49.32715.
Nechiporuk T, Urness LD, Keating MT: ETL, a novel seven-transmembrane receptor that is developmentally regulated in the heart. ETL is a member of the secretin family and belongs to the epidermal growth factor-seven-transmembrane subfamily. J Biol Chem. 2001, 276 (6): 4150-4157. 10.1074/jbc.M004814200.
Jaspars LH, Vos W, Aust G, Van Lier RA, Hamann J: Tissue distribution of the human CD97 EGF-TM7 receptor. Tissue antigens. 2001, 57 (4): 325-331. 10.1034/j.1399-0039.2001.057004325.x.
McKnight AJ, Gordon S: The EGF-TM7 family: unusual structures at the leukocyte surface. Journal of leukocyte biology. 1998, 63 (3): 271-280.
Stacey M, Chang GW, Sanos SL, Chittenden LR, Stubbs L, Gordon S, Lin HH: EMR4, a novel epidermal growth factor (EGF)-TM7 molecule up-regulated in activated mouse macrophages, binds to a putative cellular ligand on B lymphoma cell line A20. J Biol Chem. 2002, 277 (32): 29283-29293. 10.1074/jbc.M204306200.
Hadjantonakis AK, Sheward WJ, Harmar AJ, de Galan L, Hoovers JM, Little PF: Celsr1, a neural-specific gene encoding an unusual seven-pass transmembrane receptor, maps to mouse chromosome 15 and human chromosome 22qter. Genomics. 1997, 45 (1): 97-104. 10.1006/geno.1997.4892.
Formstone CJ, Barclay J, Rees M, Little PF: Chromosomal localization of Celsr2 and Celsr3 in the mouse; Celsr3 is a candidate for the tippy (tip) lethal mutant on chromosome 9. Mamm Genome. 2000, 11 (5): 392-394. 10.1007/s003350010073.
Usui T, Shima Y, Shimada Y, Hirano S, Burgess RW, Schwarz TL, Takeichi M, Uemura T: Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell. 1999, 98 (5): 585-595. 10.1016/S0092-8674(00)80046-X.
King N, Hittinger CT, Carroll SB: Evolution of key cell signaling and adhesion protein families predates animal origins. Science. 2003, 301 (5631): 361-363. 10.1126/science.1083853.
Inoue H, Lin L, Lee X, Shao Z, Mendes S, Snodgrass-Belt P, Sweigard H, Engber T, Pepinsky B, Yang L, Beal MF, Mi S, Isacson O: Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proceedings of the National Academy of Sciences of the United States of America. 2007, 104 (36): 14430-14435. 10.1073/pnas.0700901104.
Skradski SL, Clark AM, Jiang H, White HS, Fu YH, Ptacek LJ: A novel gene causing a mendelian audiogenic mouse epilepsy. Neuron. 2001, 31 (4): 537-544. 10.1016/S0896-6273(01)00397-X.
Gibert Y, McMillan DR, Kayes-Wandover K, Meyer A, Begemann G, White PC: Analysis of the very large G-protein coupled receptor gene (Vlgr1/Mass1/USH2C) in zebrafish. Gene. 2005, 353 (2): 200-206. 10.1016/j.gene.2005.05.015.
Bjarnadottir TK, Fredriksson R, Hoglund PJ, Gloriam DE, Lagerstrom MC, Schioth HB: The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics. 2004, 84 (1): 23-33. 10.1016/j.ygeno.2003.12.004.
Ramakers C, Ruijter JM, Deprez RH, Moorman AF: Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett. 2003, 339 (1): 62-66. 10.1016/S0304-3940(02)01423-4.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25 (4): 402-408. 10.1006/meth.2001.1262.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002, 3 (7): RESEARCH0034-10.1186/gb-2002-3-7-research0034.
RF was supported by the Swedish Brain Foundation (Hjärnfonden). The studies were supported by the Swedish Research Council, AFA, Svenska Läkaresällskapet, Åke Wiberg Foundation, Lars Hiertas foundation, Thurings foundation, The Royal Swedish Academy of Sciences, the Magnus Bergvall Foundation and Åhlens foundation.
TH designed the study, analyzed the data and drafted the manuscript. FO and OS performed the real-time PCR on rat, respectively mouse tissues and made the calculations. TE and JA carried out the dissection of mouse tissues. ER and RF performed the dissection of rat tissues. HBS conceived of the study and helped to draft the manuscript. RF participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.
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Haitina, T., Olsson, F., Stephansson, O. et al. Expression profile of the entire family of AdhesionG protein-coupled receptors in mouse and rat. BMC Neurosci 9, 43 (2008). https://doi.org/10.1186/1471-2202-9-43
- Adhesion Receptor
- Phylogenetic Cluster
- Hormone Binding Domain
- Epidermal Growth Factor Domain
- Black Widow Spider