Review
Evolution of GnRH ligands and receptors in gnathostomata ☆
Leonardo G. Guilgur
a,1, Natalia P. Moncaut
b,1, Adelino V.M. Canário
b, Gustavo M. Somoza
a,⁎
aLaboratorio de Ictiofisiología y Acuicultura, IIB-INTECH (CONICET-Universidad Nacional de General San Martín), IIB-INTECH, Camino de Circunvalación Laguna Km. 6, CC 164 (B7130IWA), Chascomús, Provincia de Buenos Aires, Argentina
bCentre of Marine Sciences, University of Algarve, Campus de Gambelas 8005-139, Faro, Portugal Received 20 September 2005; received in revised form 19 January 2006; accepted 14 February 2006
Available online 6 March 2006
Abstract
Gonadotropin-releasing hormone (GnRH) is the final common signaling molecule used by the brain to regulate reproduction in all vertebrates. Until now, a total of 24 GnRH structural variants have been characterized from vertebrate, protochordate and invertebrate nervous tissue. Almost all vertebrates already investigated have at least two GnRH forms coexisting in the central nervous system. Furthermore, it is now well accepted that three GnRH forms are present both in early and late evolved teleostean fishes. The number and taxonomic distribution of the different GnRH variants also raise questions about the phylogenetic relationships between them. Most of the GnRH phylogenetic analyses are in agreement with the widely accepted idea that the GnRH family can be divided into three main groups. However, the examination of the gnathostome GnRH phylogenetic relationships clearly shows the existence of two main paralogous GnRH lineages: the
‘‘midbrain GnRH”
group and the
“forebrain GnRH”group. The first one, represented by chicken GnRH-II forms, and the second one composed of two paralogous lineages, the salmon GnRH cluster (only represented in teleostean fish species) and the hypophysotropic GnRH cluster, also present in tetrapods. This analysis suggests that the two forebrain clades share a common precursor and reinforces the idea that the salmon GnRH branch has originated from a duplication of the hypophysotropic lineage. GnRH ligands exert their activity through G protein- coupled receptors of the rhodopsin-like family. As with the ligands, multiple GnRHRs are expressed in individual vertebrate species and phylogenetic analyses have revealed that all vertebrate GnRHRs cluster into three main receptor types. However, new data and a new phylogenetic analysis propose a two GnRHR type model, in which different rounds of gene duplications may have occurred in different groups within each lineage.
© 2006 Elsevier Inc. All rights reserved.
Keywords:GnRH; GnRH receptors; Vertebrates; Evolution
Contents
1. GnRH peptides structure . . . 273
2. Taxonomic and neuroanatomical distribution . . . 274
3. Phylogenetic relationships between GnRHs . . . 274
4. Two or three GnRH systems in gnathostomes? . . . 276
5. GnRH receptor structure. . . 277
6. Phylogenetic relationships between GnRHRs . . . 277
☆This invited review is published in conjunction with the publications from the Symposium“Comparative Neuroendocrinology—Integration of Hormonal and Environmental Signals in Vertebrates and Invertebrates”presented at the 15th International Congress of Comparative Endocrinology, May 23-28, 2005, at Boston, MA, USA. Organizer: Dr. Vance Trudeau, University of Ottawa, Canada.
⁎Corresponding author. Tel.: +54 2241 430323; fax: +54 2241 424048.
E-mail address:[email protected](G.M. Somoza).
1Both authors equally contributed to this manuscript.
1095-6433/$ - see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.cbpa.2006.02.016
7. GnRHRs tissue distribution . . . . 277
8. GnRH and GnRHRs final considerations . . . . 279
Acknowledgements . . . . 279
References . . . . 279
1. GnRH peptides structure
Gonadotropin-releasing hormone (GnRH) represents the main step in the cascade of hormones participating in the coordination of reproductive physiology (Schally et al., 1973).
GnRH is a neuropeptide that stimulates the synthesis and release of pituitary gonadotropins in vertebrates from lampreys to humans (Conn and Crowley, 1994; Zohar et al., 1995; Sower and Kawauchi, 2001). This molecule is synthesized by neurons located in specific brain areas and reaches the pituitary gland via a portal system in tetrapods (Fink, 1988) or by direct innervation of the gonadotropes, or in close vicinity to them in teleostean fishes (Anglade et al., 1993; Yamamoto et al., 1995).
GnRH was originally characterized from mammalian nervous tissues (Matsuo et al., 1971; Burgus et al., 1972) and considered to be a unique molecular form. However, a few years later, Miyamoto et al. (1983) and Sherwood et al. (1983) reported the presence of GnRH molecular variants in other vertebrates. Up to now, a total of 24 different molecular forms have been characterized from brain tissue of different
vertebrates and invertebrates (Lethimonier et al., 2004).
However, novel GnRH variants are likely to be discovered since new GnRH-like peptides have been detected by immunological methods in animal groups as diverse as gastropods, bivalves and cnidarians (Goldberg et al., 1993;
Pazos and Mathieu, 1999; Young et al., 1999; Anctil, 2000). All currently known GnRH variants are presented in Table 1.
The peptides belonging to the GnRH family share the following characteristics: all are decapeptides (except for octopus GnRH which has 12 amino acids; Iwakoshi et al., 2002), with residues 1, 4, 9 and 10 perfectly conserved and modified amino- (pGlu) and carboxy-terminus (NH
2). It is important to note that these GnRH forms are commonly known by the name of the species in which they were first isolated, except for the first characterized GnRH from mammalian hypothalamic tissues (pig and sheep), now referred to as mammalian GnRH (mGnRH) and the tunicate GnRH variants (Adams et al., 2003). However, there have been proposals for different nomenclatures (Fernald and White, 1999; Dubois et al., 2002).
Table 1
Primary structure of vertebrate, protochordate and invertebrate GnRH forms
GnRH variant 1 2 3 4 5 6 7 8 9 10
Verterbrates
Mammalian GnRH pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly-NH2 Matsuo et al., 1971; Burgus et al., 1972
Chicken GnRH-I – – – – – – – Gln – – Miyamoto et al., 1983
Rana GnRH – – – – – – – Trp – – Yoo et al., 1984
Seabream GnRH – – – – – – – Ser – – Powell et al., 1994
Salmon GnRH – – – – – – Trp Leu – – Sherwood et al., 1983
White fish GnRH-I – – – – – – Met Asn – – Adams et al., 2002
Guinea pig GnRH – Tyr – – – – Val – – – Jiménez-Liñán et al., 1997
Pejerrey GnRHa – – – – Phe – – Ser – – Okubo et al., 2000a; Montaner et al., 2001a
Chicken GnRH-II – – – – His – Trp Tyr – – Miyamoto et al., 1984
Catfish GnRH – – – – His – – Asn – – Ngamvongchon et al., 1992
Herring GnRH – – – – His – – Ser – – Carolsfeld et al., 2000
Dogfish GnRH – – – – His – Trp Leu – – Lovejoy et al., 1992
Lamprey GnRH III – – – – His Asp Trp Lys – – Sower et al., 1993
Lamprey GnRH I – – Tyr – Leu Glu Trp Lys – – Sherwood et al., 1986
Chordates and non-chordates
Turnicate GnRH-I – – – – Asp Tyr Phe Lys – – Powell et al., 1996
Turnicate GnRH-II – – – – Leu Cys His Ala – – Powell et al., 1996
Turnicate GnRH-III – – – – – Glu Phe Met – – Adams et al., 2003
Turnicate GnRH-IV – – – – Asn Gln – Thr – – Adams et al., 2003
Turnicate GnRH-V – – – – – Glu Tyr Met – – Adams et al., 2003
Turnicate GnRH-VI – – – – Lys Gly Tyr Ser – – Adams et al., 2003
Turnicate GnRH-VII – – – – – Ala – Ser – – Adams et al., 2003
Turnicate GnRH-VIII – – – – Leu Ala – Ser – – Adams et al., 2003
Turnicate GnRH-IX – – – – Asn Lys – Ala – – Adams et al., 2003
Turnicate GnRH – – Phe – Asn Gly Trp His – – Iwakoshi et al., 2002
Asn Tyr
a Pejerrey GnRH (pjGnRH) is also known as medaska GnRH (mdGnRH).
In addition to this diversity, and although it was initially considered that a single molecular form was expressed in all vertebrate brains, it is now clear that most vertebrate species express more than one GnRH form encoded by different genes (Fernald and White, 1999; Dubois et al., 2002; Vickers et al., 2004). The simultaneous presence of multiple GnRH variants in the brain has been demonstrated in every studied vertebrate phyla: jawless fish (Sherwood et al., 1986; Sower et al., 1993), elasmobranchs (Lovejoy et al., 1991b, 1992), teleostean fishes (Ngamvongchon et al., 1992; Powell et al., 1994, 1997; Weber et al., 1997; Carolsfeld et al., 2000; Montaner et al., 2001a;
Vickers et al., 2004), amphibians (Conlon et al., 1993), reptiles (Lovejoy et al., 1991a), birds (Miyamoto et al., 1983, 1984) and mammals (Kasten et al., 1996; White et al., 1998).
All vertebrate GnRH peptides to date originate from prepro- GnRH precursors that share a common structure comprising: a signal peptide of about 20–25 residues, a GnRH peptide of 10 residues, a conserved processing tripeptide (Gly–Lys–Arg) and a GnRH-associated peptide or GAP in 40 – 50 residues length.
Such a structure was originally described for mGnRH (Adelman et al., 1986) and then confirmed in many other vertebrate species (Klungland et al., 1992; Dunn et al., 1993; Bogerd et al., 1994; Coe et al., 1995; Lin and Peter, 1996; Jiménez-Liñán et al., 1997; Chow et al., 1998; White et al., 1998; Suzuki et al., 2000; Wang et al., 2001b; Amano et al., 2002).
22. Taxonomic and neuroanatomical distribution
Taking into consideration the taxonomic and anatomical distribution of GnRH variants in tetrapods, two forms have been identified in central nervous system structures: cGnRH-II in midbrain areas and a form related to the control of the pituitary gonadotropes in the anterior brain (Muske, 1993, 1997). In mammals this anterior brain variant can be either mGnRH, [Hyp
9]mGnRH (a hydroxylated variant of mGnRH) (Gautron et al., 1991), or gpGnRH (Kasten et al., 1996; Jiménez-Liñán et al., 1997; Gao et al., 2000; Montaner et al., 2001b); in birds and reptiles it is represented by cGnRH-I (Lovejoy et al., 1991a;
Miyamoto et al., 1983, 1984), and finally in amphibians by mGnRH or rGnRH (Iela et al., 1996; Chartrel et al., 1998; Yoo et al., 2000).
The same differential distribution pattern is also seen in some of the early evolved teleostean species where the hypophyso- tropic GnRH variant is represented by mGnRH in Anguilli- formes (King et al., 1990; Chiba et al., 1999; Okubo et al., 1999), mGnRH or sGnRH in Osteoglossiformes (O'Neill et al., 1998; Okubo and Aida, 2001), sGnRH in Salmoniformes (Okuzawa et al., 1990; Amano et al., 1991) and Cypriniformes (Kah et al., 1986; Kim et al., 1995), and cfGnRH in Siluriformes (Zandbergen et al., 1995; Dubois et al., 2001). However there is an increasing number of teleostean species where three GnRH
variants have been identified and localized. All these species express cGnRH-II, sGnRH and a third form which can be considered as group specific: hrGnRH in Clupeiformes, wfGnRH in Salmoniformes, pjGnRH in Atheriniformes, Synbranchiformes, Beloniformes and Cyprinidontiformes, and sbGnRH in Characiformes, Perciformes, Pleuronectiformes and Tetraodontiformes (Somoza et al., 2002; Lethimonier et al., 2004; Sherwood and Adams, 2005).
In teleostean fishes these GnRH variants also show a differential neuroanatomical distribution. Chicken GnRH-II is expressed by neurons located at the tegmentum of the midbrain (MT), sGnRH by neurons from the terminal nerve ganglion (TNG) and the third form mainly by preoptic neurons (Gothilf et al., 1996; Okuzawa et al., 1997; Fernald and White, 1999;
Okubo et al., 2000a; Stefano et al., 2000; González-Martínez et al., 2001; Amano et al., 2002; Zmora et al., 2002; Vickers et al., 2004). Although the distribution of the three GnRH forms was first considered to be restricted to specific brain areas, González-Martínez et al. (2001) described for the first time in the European sea bass, Dicentrarchus labrax, an overlapped distribution of sGnRH and sbGnRH expressing cells from the olfactory bulbs to the preoptic region and since then similar distribution schemes have been reported in many other species, including the white fish, Coregonus clupeaformis (Vickers et al., 2004), the Atlantic croaker, Micropogonias undulatus (Mohamed et al., 2005), a South-American cichlid Cichlasoma dimerus (Pandolfi et al., 2005) and the meagre Argyrosomus regius (Confente et al., 2005). In this context, and although very few species have been analyzed in detail as to location, the overlapping of GnRH expressing neurons in the teleostean forebrain may be the rule instead of an exception.
3. Phylogenetic relationships between GnRHs
A few years ago, White et al. (1998) proposed a phylogenetic tree of GnRH prepro-hormones from bony fish and mammalian species in which the GnRH family grouped into three main clusters. The topology of the tree has not been affected by the inclusion of newly discovered prepro-hormones and it has been widely accepted (Okubo et al., 1999, 2000a; Okubo and Aida, 2001; Dubois et al., 2002; Lethimonier et al., 2004; Vickers et al., 2004). In this tree, the so called GnRH I group contains all GnRH forms related to pituitary control and expressed by neurons located in the preoptic area, the GnRH II group contains all cGnRH-II forms expressed by midbrain neurons, and the GnRH III group includes all sGnRH forms located either in neurons from the olfactory region and the anterior telencephalon of teleosts. A logical implication of the White et al. (1998) tree was the existence of three paralogous GnRH genes in teleosts and, therefore, either a third GnRH variant is still waiting to be discovered in tetrapods, or its gene has been lost in the tetrapod lineage. Indeed, there is immunological evidence for the presence of a sGnRH-like form in amphibians and mammals (Cariello et al., 1989; Montaner et al., 1998, 1999).
Many of the phylogenetic analyses that have been carried out have focussed on showing the existence of three paralogous
2More information about the different forms of GnRH in terms of pep- tide sequence and cDNA organization can be obtained on the web at the following addresses: http://www.sanger.ac.uk/cgi-bin/Pfam/getalignment.pl?
name=GnRH&acc=PF00446&type=full&format=link, and http://www.sanger.
ac.uk/cgi-bin/Pfam/getallproteins.pl?name=GnRH&acc=PF00446&verbose=
true&type=full&domain-view=all&zoom-factor=0.5&list=view+graphic.
lineages, without further enquiry into the origin of these groups of molecules. In addition, some studies have also focused on suggesting the existence of three different GnRH systems with distinct physiological functions in the teleost lineage (Parhar et al., 1998; Dubois et al., 2002).
In a recent study, Guilgur et al. (unpublished) performed an extensive phylogenetic analysis using the maximum parsimony method (Fitch and Markowitz, 1970) using the PHYLIP software (Felsenstein, 1989), based on the Clustal W alignment (Thompson et al., 1994) of the cDNA sequences of 84 prepro-GnRHs from gnathostomes (Fig. 1).
This analysis has yielded two main paralogous GnRH
lineages in the gnathostomes: the ‘‘midbrain GnRH” and the “forebrain GnRH” lineages. The former corresponds to the GnRH II group defined by White et al. (1998). The
“forebrain GnRH” lineage diverges in two paralogous clades, the sGnRH clade (GnRH III group), only represented by teleostean species, and the hypophysotropic clade (GnRH I group). This suggests that the two clades grouped into the
“forebrain GnRH” lineage share a common precursor.
Furthermore, the analysis reinforces the idea that the sGnRH branch originated from the hypophysotropic lineage as suggested by O'Neill et al. (1998), Okubo and Aida (2001), and Dubois et al. (2002).
100
pjO. latipes sbM. cephalus
pjO. bonariensis sbA. burtoni
sbO. niloticus sbV. moseri sbR. canadum
sbM. undulatus
sbC. nebulosus sbP. major
sbS. aurata SbM. saxatilis sbD. labrax
817 995
mA. japonica wfC. clupeaformis
hrA. sapidissima cfC. gariepinus 932
cIG. gallus
mR. norvegicus gpC. porcellus mT. belangeri mS. scrofa mH. sapiens
810
mX. laevis
mR. catesbeiana rR. dybowskii
988 915
755
cIIA. japonica cIIS. jardinii
cIIM. Cephalus
cIIV. moseri cIIR. canadumcIIS. aurata
cIIS. ocellatus cIIC. nebulosus
cIIM. undulatus cIIM. saxatilis
cIID. labrax cIIA. burtoni cIIO. niloticus
cIIM. albus cIIO. latipes
cIIO. bonariensis cIIC. clupeaformis
cIIO. mykiss
809 cIIC. gariepinus cIID. rerio cIIC. carpio cIIC. auratus
cIIR. rutilus
858 cIIE. macularius cIIT. natanscIIR. catesbeiana
cIIT. vulpeculal
910 cIIS. murinus
cIIT. belangeri cIIH. sapiens
cIIM. mulatta
1000 1000
995 931
sS. jardinii sD. rerio sC. auratus
sC. carpio sR. rutilus
1000
sC. clupeaformis sS. fontinalis
sS. trutta sS.salar
sO. nerka sO. mykiss
sO. masou
1000
sO. bonariensissO. latipessM. cephalus sA. burtoni
sO. niloticus sR. canadum
sC. nebulosus sM. undulatus
sS. ocellatus sP. notatus sV. moseri
sS. aurata sP. major sD. labrax 949
920 898
sbS. ocellatus
Fig. 1. Unrooted tree showing GnRH variants within the gnathostomate lineage. The two larger circles delimit the“midbrain GnRH”and the“forebrain GnRH”clades.
Bootstrap values are indicated in the main branches. The smaller circles within the“forebrain GnRH”group represent the sGnRH clade (up) and the hypophysotropic clade (below). Abbreviations: cI: chicken GnRH-I; cII: chicken GnRH-II; cf: catfish GnRH; gp: guinea pig GnRH; hr: herring GnRH; m: mammalian GnRH; pj:
pejerrey GnRH; r: rana GnRH; s: salmon GnRH; sb: sea bream GnRH; wf: white fish GnRH. A. burtoni:Astatotilapia burtoni; A. japonica:Anguilla japonica; A.
sapidissima:Alosa sapidissima; C. auratus:Carassius auratus; C. carpio:Cyprinus carpio; C. clupeaformis:Coregonus clupeaformis;C. gariepinus:Clarias gariepinus; C. nebulosus:Cynoscion nebulosus; C, porcellus:Cavia porcellus; D. labrax:Dicentrarchus labrax; D. rerio:Danio rerio; E. macularis:Eublepharis macularius; G. gallus:Gallus gallus; H. sapiens:Homo sapiens; M. albus:Monopterus albus; M. cephalus:Mugil cephalus; M. mulatta:Macaca mulatta; M. saxatilis:
Morone saxatilis; M. undulatus:Micropogonias undulatus; O. bonariensis:Odontesthes bonariensis; O. latipes:Oryzias latipes; O. masou:Oncorhynchus masou; O.
mykiss:Oncorhynchus mykiss;O. nerka:Oncorhynchus nerka; O. niloticus:Oreochromis niloticus; P. major:Pagrus major; P. notatus:Porichthys notatus; R.
canadum;Rachycentron canadum; R. catesbeiana:Rana catesbeiana; R. dybowskii:Rana dybowskii; R. norvegicus:Rattus norvegicus; R. rutilus:Rutilus rutilus; S.
aurata:Spaurus aurata; S. fontinalis:Salvelinus fontinalis; S. jardinii:Scleropages jardinii; S. Ocellatus:Sciaenops ocellatus; S. murinus:Suncus murinus; S. salar:
Salmo salar; S. scrofa:Sus scrofa; S. trutta:Salmo trutta; T. natans:Typhlonectes natans; T. belangeri:Tupaia belangeri; T. vulpecula:Trichosurus vulpecula; V.
moseri:Verasper moseri; X. laevis:Xenopus laevis.
Nevertheless, the time of emergence of the sGnRH clade is still a matter of debate. Has the duplication leading to sGnRH occurred within the teleostean lineage or before the divergence of fish and tetrapods? Some authors have suggested that if the duplication was recent, the sGnRH forms from different fish species would have been expected to group with one of the hypophysotropic GnRH forms in fish (White et al., 1998;
Okubo et al., 1999; Okubo and Aida, 2001), with the implication, stated above, that a third form with similar characteristics to sGnRH should be present in the central nervous system of different vertebrates, or, otherwise, absent as a result of gene loss during tetrapod evolution.
An alternative hypothesis is that the duplication event that led to the emergence of sGnRH happened within the teleostean lineage. This hypothesis is based on the following observations:
a) The mGnRH form appears in early evolved fish. It is evidenced by the presence of mGnRH in basal non-teleost fish species (Sherwood et al., 1991; Lescheid et al., 1995).
b) The presence of sGnRH was demonstrated in some bonytongue species, Osteoglossomorpha (O'Neill et al., 1998; Okubo and Aida, 2001), the link between ancient bony fish and euteleost groups (Inoue et al., 2001). Other species from the same order contain mGnRH together with cGnRH- II (O'Neill et al., 1998).
c) There are larger gene families in teleosts fish (Amores et al., 1998; Wittbrodt et al., 1998; Ohno, 1999; Taylor et al., 2003). It is also thought that whole genome duplication occurred in the teleost fish lineage (Chen et al., 2004;
Hoegg et al., 2004; Van de Peer, 2004). For example, for many gene families, two paralogous copies are found in zebrafish and pufferfish, where only one ortholog is found in tetrapods (Wittbrodt et al., 1998). Another clear example is seen in some tetraploid species where two sGnRH or cGnRH-II genes have been demonstrated (Lin and Peter, 1997; Ferriere et al., 2001; Gray et al., 2002; Uzbekova et al., 2002).
d) If sGnRH has emerged either from point mutation from the mGnRH gene or after duplication of this gene and subsequent divergence, this would imply that the tran- scription factors involved should be conserved or be similar between the corresponding promoters. In this context, reporter gene studies confirmed the importance of this region for cell specific expression in zebrafish, because the promoter of human mGnRH was demonstrated to be capable of driving cell specific reporter gene expression in transgenic zebrafish (Torgersen et al., 2002). Recently Kuo et al. (2005) hypothesized that, after the separation of ray-fin and lobe-fin fishes, the ancestor of the hypophysiotropic GnRH form was duplicated to give rise to a hypophysiotropic GnRH ancestor (mGnRH?) and sGnRH.
e) Although reports from our and other groups have shown evidence for the presence of a third sGnRH-like variant in mammals (Montaner et al., 1998, 1999; Yahalom et al., 1999) detailed studies have failed to purify and therefore to
demonstrate its presence (Montaner et al., 2001b, 2002). On this respect, recent studies on genome sequencing in human and mouse have failed to identify sGnRH in these species (Hapgood et al., 2005; Kuo et al., 2005).
Besides the above mentioned observations, a deep phylogenetic analysis is needed to establish the time of origin of the “fish-specific” GnRH genes to know if the duplication round that led to the occurrence of these genes occurred before the divergence of fish and tetrapods or during the proposed fish-specific genome duplication event after the tetrapod split.
4. Two or three GnRH systems in gnathostomes?
Although in any particular species, “forebrain GnRH” can differentiate into two clusters of neurons expressing different GnRH variants with different physiological functions, leading to some authors to postulate the existence of three GnRH systems, there are anatomical, embryological and phylogenetic data supporting the idea of only two GnRH systems in gnathostomes:
a) Anatomical data: The distribution of cells containing sGnRH or sbGnRH overlaps from the olfactory bulbs to the preoptic region in several teleost species (González-Martínez et al., 2001; Vickers et al., 2004; Mohamed et al., 2005; Confente et al., 2005; Pandolfi et al., 2005). The anatomical characteristics of this distribution are quite similar to those observed in vertebrate species expressing only one GnRH variant in forebrain structures. For example, in the African catfish, two distinct GnRH cell populations exist: a terminal nerve cell group and a ventral forebrain cell group (Dubois et al., 2001). In the rhesus macaque there are two different migrating immunoreactive GnRH cell groups, with distinct temporal expression and differences in their morphology and brain distribution (Quanbeck et al., 1997; Terasawa et al., 2001). Similar observations have also been reported in mouse (Skynner et al., 1999).
b) Embryological data: Although some authors proposed that the neurons expressing the anterior GnRH variants have two different embryological origins (Parhar, 1997; Parhar et al., 1998; Chiba et al., 1999; Pandolfi et al., 2002), other studies have demonstrated that both sGnRH and sbGnRH cells were first detected in the olfactory region and migrate during early development in a rostro-caudal direction to reach their final positions along a continuum from the olfactory bulbs to the hypothalamus (White and Fernald, 1998a; Whitlock et al., 2003, 2005; González-Martínez et al., 2004b; Okubo et al., 2004).
c) Phylogenetic data: The phylogenetic analysis shows two main lineages of GnRH in vertebrates, the “forebrain GnRH”
group and the “midbrain GnRH” group. The expression of
two different GnRH genes in forebrain structures only occurs
in the teleost lineage and may be the result of the process of
subfunctionalization (Force et al., 1999; Lynch and Force,
2000).
Taken together these data support the idea of two GnRH ligand systems in gnathostomes as originally proposed by Muske (1993, 1997).
5. GnRH receptor structure
The events leading to GnRH-stimulated gonadotropin synthesis and release from the anterior pituitary are mediated by GnRH receptors (GnRHRs). Therefore knowledge of GnRHR structures, their interactions with GnRH and GnRH analogs, and their regulation is essential to the understanding of the physiology of reproduction.
GnRHRs belong to the rhodopsin-like G protein-coupled receptor (GPCR) family. These receptors show three main functional domains: an N-terminal extracellular domain, seven α-helical transmembrane (TMs) domains connected by hydro- philic intra- and extracellular loops and a C-terminal cytoplas- matic domain. The extracellular domains and superficial regions of the TMs are usually involved in the binding events. The TMs are believed to be involved in receptor configuration and the C- terminal, together with the cytoplasmatic regions from the TMs, mediates effector binding, propagation of signaling events, desensitization and internalization (McArdle et al., 2002; Millar et al., 2004).
In 1992 the first GnRHR was cloned from a murine gonadotrope cell line, the αT3-1 cells, (Reinhart et al., 1992;
Tsutsumi et al., 1992) and since then the cDNA sequences from other mammalian and nonmammalian vertebrates have been cloned and characterized.
However, the presence of multiple GnRH forms suggested that more than one GnRHR may exist in a given species. In fact, within the last few years many reports have been published demonstrating that, in parallel with the expression of multiple ligand forms, individual vertebrate species express multiple GnRHRs: three GnRHRs in bullfrog, Rana catesbeiana (Wang et al., 2001a) and in medaka, Oryzias latipes (Okubo et al., 2001; Okubo et al., 2003); two in primates (Millar et al., 2001;
Neill et al., 2001), in the goldfish, Carassius auratus (Illing et al., 1999) and in the African catfish, Clarias gariepinus (Bogerd et al., 2002); and five in the European sea bass (Moncaut et al., 2005a). Also, GnRHRs have been characterized in protochor- dates and agnathans; Kusakabe et al. (2003), showed the presence of multiple GnRHRs in Ciona intestinalis and subsequently Tello et al. (2005) isolated two additional GnRHRs in the same species and showed that all four GnRHRs responded to homologous GnRH peptides. Also recently, a GnRHR was cloned from the lamprey, Petromyzon marinus that belongs to the oldest vertebrate lineage (Silver et al., 2005).
6. Phylogenetic relationships between GnRHRs
Troskie et al. (1998) analyzed the phylogenetic relationships of the GnRHR extracellular domain 3 (EC3) and proposed that all vertebrate GnRH receptors could be grouped in two main types: Type I, which has IA and IB subtypes, grouped with the mammalian GnRH pituitary receptors and included GnRHRs from tetrapod and teleost species. Type II included only
receptors from tetrapods. With the finding of new GnRHRs from different vertebrate species, phylogenetic relationships have been re-evaluated suggesting that all vertebrate GnRHRs cluster into three main receptor types (Millar et al., 2004). This proposal was based on criteria such as gene organization, existence of a C-terminal tail, and the three clade-phylogenetic tree for the ligand. However, considering that the three-GnRHR model lacked clear phylogenetic, structural or functional support, we have recently proposed a parsimonious two GnRHR type model, which includes mammalian receptor types 1 and 2 (Moncaut et al., 2005a). Within each type, specific duplication events (in some cases more than one) occurred early in evolution in different taxa, such as in the amphibians (Fredriksson et al., 2004) and the ray-finned fishes (Taylor et al., 2003) (Fig. 2).
The analysis of the primary structure of the translated GnRHR proteins shows that the differences in size of the C- terminal tail as one of the main features to group these receptors, and this classification are according to our phylogenetic results.
All vertebrate Type 1 receptors have the shortest tail, comprising between 36 and 56 amino acids, with the extreme case of mammalian Type 1 receptor that completely lack this part of the molecule. In contrast, Type 2 receptors have longer carboxyl terminal tails, with 54 to 79 amino acids in length (Moncaut et al., 2005a). Thus, from an evolutionary point of view, it seems that there is a tendency for the progressive loss of this region of the protein by the Type 1 receptor, with expected implications in the mechanism of signal transduction (see review by Millar et al., 2004). The presence of a C-terminal tail in C. intestinalis GnRHRs (Kusakabe et al., 2003; Tello et al., 2005) is also indicative that the ancestral vertebrate GnRHR had a C-terminal tail, and that its absence in mammalian GnRHRs is only a derived characteristic.
7. GnRHRs tissue distribution
Analysis of GnRHR gene expression supports the idea that GnRH actions are not limited to the central nervous system and the pituitary gland. GnRHRs are expressed in peripheral tissues related to senses, reproduction and homeostasis suggesting involvement in these functions, although testing of this hypothesis is still required.
The distribution of GnRH receptors in the central nervous
system and pituitary gland is evident in every organism. In some
particular cases, as in the bullfrog and catfish, where two
different types of receptors were found, differential expression
has been described in these tissues (Wang et al., 2001a; Bogerd
et al., 2002). A detailed characterization has been made to
determine the type of pituitary cell expressing the receptors,
which clearly showed that the gonadotropes are not the
exclusive targets of GnRHs. In the Nile tilapia, Oreochromis
niloticus, three GnRH receptors are expressed, often coexpres-
sing in lactotropes, somatotropes, thyrotropes, melanotropes,
corticotropes and somatolactin cells (Parhar et al., 2005). The
goldfish receptors are both highly expressed in gonadotropes
with a minor overlap with somatotropes (Illing et al., 1999). In
the European sea bass, GnRH receptor 2A is evident in all LH
and some FSH cells but not in somatotropes (González- Martínez et al., 2004a).
Most vertebrates express GnRHR in the gonads: humans, rats, mice and teleost species. Whenever the receptor expression was not detected, as in the guinea pig, it could have been due to the particular stage in reproductive period or that a still unknown receptor type (Fujii et al., 2004). In the African catfish, only one of the receptors showed expression in the gonads, particularly in the ovary, and with differences along the reproductive cycle (Bogerd et al., 2002). The presence of GnRH receptors in the gonads has also been confirmed by binding studies (Pati and Habibi, 1993), suggesting a direct effect of GnRHs on sex steroid production and gametogenesis.
The expression of GnRHRs in tissues not related to the reproductive axis is of special interest in particular those related to osmoregulation. In the European sea bass, for example, Type 1 receptors are expressed in the gills and in the kidney (Moncaut et al., 2005a); similar to what was reported for the masu salmon, Oncorhynchus masou (Jodo et al., 2003). Furthermore, in the African cichlid, Haplochromis burtoni, the kidney expresses at
least one form of GnRH (White and Fernald, 1998b) while cGnRH-II was found to be expressed in kidney and gills of the European sea bass (Moncaut et al., unpublished results). Since GnRHs and their receptors have never been associated with osmoregulation, this potential link will have to be investigated as they may underlie a possible new GnRH function.
Expression of GnRH receptors Type 1 has also been found in tissues related to chemical sensory perception such as the olfactory epithelium of the European sea bass (Moncaut et al., 2005a) and Japanese eel (Okubo et al., 2000b). In addition, significant expression of these receptors was reported in the eyes of rainbow trout (Madigou et al., 2000), European sea bass (Moncaut et al., 2005a) and Japanese eel (Okubo et al., 2000b).
As some immunoreactive GnRH fibers that clustered within the medial component of the olfactory nerve project to the retina, it has been suggested that perhaps GnRH facilitates visual and olfactory perception during sexual interactions (Nevitt et al., 1995).
The presence of GnRHRs in most tissues, including neural complex/brain and gonads of the tunicate, C. intestinalis and in the pituitary and testes of the agnathan P. marinus, is an
FS686 Sa
dlGnRHR-2A
Ms 68
On2 Sd 59
78 82
FS1435 On3 Ol1
dlGnRHR-2C 53
61 97
94
FS3910 dlGnRHR-2B
Ol3
100 83
RcI Rd1 Rr1
54 100 92 Xl2 Tn
RcIII Rd3
Rr3
98 100 98 79
59 HumanII
Mm2 AsCjII
86 100
61 Aj
Ol2
On1 82
dlGnRHR-1B FS2243
50
94 Cg2CaA
58 Oma4 FS553
dlGnRHR-1A
98
Cg1Ca B
54 73
OmOma1
100
99
Gg Em
77
Xl1 Rr2 Rd2
RcII 86
99 100 90
92 Cp Rn
Mm 75
HumanI 95 Mr1
Ec Cc
Oa
Bt
Bb 95 98 86 85 57 100
Type 1
Type 2
Fig. 2. Unrooted tree showing GnRHRs within the gnathostomate lineage. The two larger Venn diagrams delimit type I and type II receptors; the included smaller diagrams delimit the fish clades. The tree was generated using PAUP software using the Parsimony criterion. Bootstrap values are indicated in the nodes. Organism abbreviations: Aj,Anguilla japonica; As,Aethiops sabeus; Bb,Bubalus bubalis; Bt;Bos taurus; CaA, CaB,Carassius auratus; Cc,Canis canis; Cg1, Cg2,Clarias gariepinus; CjII,Callitrix jacchus; CpCavia porcellus; dl,Dicentrarchus labrax; Ec,Equus caballus; Em,Eublepharis macularius;FS,Fugu rubripesscaffold;Gg, Gallus gallus; Mm,Mus musculus;Mm2,Macaca mulata; Mr, Macaca radiata; Ms,Morone saxatilis, Oa,Ovis aries; Ol1, Ol2, Ol3,Oryzias latipes; Om, Oncorhynchus mykiss; Oma1, Oma4,Oncorhynchus masou; On1, On, On3,Oreochromis niloticus; RcI, RcII, RcIII,Rana catesbeiana; brown frog, Rd1, Rd2, Rd3, Rana dybowskii; Rn,Rattus norvegicus; Rr1, Rr2, Rr3,Rana ridibunda; Sa,Sparus auratus; Sd,Seriola dumerilii; Tn,Typhlonectes natans; Xl1, Xl2,Xenopus laevis.
Reproduced by permission. © Society for Endocrinology (2005). The original publication isMoncaut et al., 2005a,b. See the reference section for details.
indication of the ancestral function of GnRH system in these tissues (Silver et al., 2005; Tello et al., 2005). In this context the expression of the various receptors in the central nervous system and gonads results in a common feature of the GnRH system, reflecting some ancestral functions. However, at peripheral levels specialized functions have evolved independently.
8. GnRH and GnRHRs final considerations
In conclusion, the existence of multiple GnRH forms together with numerous GnRHRs indicates that a complex interplay occurs between ligands and receptors in the regulation of pituitary hormone secretion. The fact that GnRHRs have a widespread tissue distribution is suggestive that the different GnRH forms are also playing a role in the regulation of a wide range of physiological functions either in an autocrine or paracrine manner.
The assumption of two main GnRH ligand systems in gnathostomes is based on anatomical, embryological and phylogenetic data. Although, there is much less information on the anatomical distribution of GnRHRs and there is almost no comparative data on their ontogenetic development, the phylogenetic analysis of GnRHR sequences has allowed the prediction of the existence of two main GnRHRs lineages.
Acknowledgements
We would like to thank the Society of Endocrinology for the permission to reproduce Fig. 2. We are also indebted to Dr.
Marina Clemente and Lic. Marina Uhart for their help. This work was supported in part by grants from ANPCYT (Pict 01- 12168) and CONICET (PIP 5425) to G.M.S.; and from the European Commission QLRT-2000-01465 and QLRT-1999- 31365 to A.V.M.C.
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