Luteinizing Hormone/Chorionic Gonadotropin Bioactivity in the Common Marmoset (Callithrixjacchus) is Due to a Chorionic Gonadotropin Molecule with a Structure Intermediate between Human Chorionic Gonadotropin and Human Luteinizing Hormone

Simula, A.P.; Amato, F.; Faast, Renate; Lopata, Alexander; Berka, Jennifer L.; Norman, Robert J.

doi:10.1095/biolreprod53.2.380

Cited by 34 publications

(28 citation statements)

References 35 publications

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“…Predicted sizes of the signal peptide are the same in each of the CG β-subunits as well as the LH β-subunit, in agreement with direct determinations by others (Simula et al, 1995). Mature squirrel monkey CG β-subunit is 143 amino acids in length, compared to human CGβ that is 145 amino acids in length.…”

Section: Squirrel Monkey and Owl Monkey Chorionic Gonadotropin β-Subusupporting

confidence: 86%

Molecular cloning of pituitary glycoprotein α-subunit and follicle stimulating hormone and chorionic gonadotropin β-subunits from New World squirrel monkey and owl monkey

Scammell

Funkhouser

Moyer

et al. 2008

General and Comparative Endocrinology

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The goal of this study was to characterize the gonadotropins expressed in pituitary glands of the New World squirrel monkey (Saimiri sp.) and owl monkey (Aotus sp.). The various subunits were amplified from total RNA from squirrel monkey and owl monkey pituitary glands by reverse transcription-polymerase chain reaction and the deduced amino acid sequences compared to those of other species. Mature squirrel monkey and owl monkey glycoprotein hormone α-polypeptides (96 amino acids in length) were determined to be 80% homologous to the human sequence. The sequences of mature β subunits of follicle stimulating hormone (FSHβ) from squirrel monkey and owl monkey (111 amino acids in length) are 92% homologous to human FSHβ. New World primate glycoprotein hormone α-polypeptides and FSHβ subunits showed conservation of all cysteine residues and consensus N-linked glycosylation sites. Attempts to amplify the β-subunit of luteinizing hormone from squirrel monkey and owl monkey pituitary glands were unsuccessful. Rather, the β-subunit of chorionic gonadotropin (CG) was amplified from pituitaries of both New World primates. Squirrel monkey and owl monkey CGβ are 143 and 144 amino acids in length and 77% homologous with human CGβ. The greatest divergence is in the C terminus, where all four sites for O-linked glycosylation in human CGβ, responsible for delayed metabolic clearance, are predicted to be absent in New World primate CGβs. It is likely that CG secreted from pituitary of New World primates exhibits a relatively short half-life compared to human CG.

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Section: Squirrel Monkey and Owl Monkey Chorionic Gonadotropin β-Subusupporting

confidence: 86%

Molecular cloning of pituitary glycoprotein α-subunit and follicle stimulating hormone and chorionic gonadotropin β-subunits from New World squirrel monkey and owl monkey

Scammell

Funkhouser

Moyer

et al. 2008

General and Comparative Endocrinology

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“…Its small size and easy reproduction in captivity are considered an advantage for studies in non-human primates (Smith et al 2001, Zuehlke & Weinbauer 2003. Marmoset placental CG has been the subject of several studies in the past (Hobson & Wide 1981, Saunders et al 1987, Rosenbusch et al 1994, Simula et al 1995, whereas the genomic sequence of mLH was unknown. In the present work we used intergenic PCR to demonstrate the existence of both mCG and mLH subunit genes, separated by an intronic sequence of approximately 20 kb, with CG placed 5 of the LH gene.…”

Section: Discussionmentioning

confidence: 99%

“…Using oligonucleotides published previously by Simula et al (1995) and suitable for amplification of mCG mRNA from placental tissue (Fig. 1, I forward/II reverse), we were able to amplify mCG mRNA from the pituitary of the common marmoset .…”

Section: Search For Lh Mrna Expression In the Pituitarymentioning

confidence: 99%

“…Sequence information for many primate gonadotrophins is available today (Maston & Ruvolo 2002), mostly from Old World monkeys (Schmidt et al 1999). In some species, such as the marmoset monkey (Callithrix jacchus), an important animal model for human reproduction, CG has already been characterised and cloned (Hobson & Wide 1981, Simula et al 1995 from the trophoblast cells of the placenta, whereas the sequence and pattern of expression of the LH subunit remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus)

Müller¹,

Simoni²,

Pekel³

et al. 2004

Journal of Molecular Endocrinology

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The pituitary gonadotrophins LH and FSH are responsible for regulation of gametogenesis in the testis and ovary. Chorionic gonadotrophin (CG), a third closely related glycoprotein hormone derived by gene duplication of the LH gene and secreted by the placenta in primates, is essential for the rescue of the corpus luteum and maintenance of pregnancy. We have recently shown that marmoset (m) CG mRNA is highly expressed in the pituitary of the common marmoset (Callithrix jacchus) and that LH is less active than human CG in activating the human LH receptor lacking exon 10. To investigate further which gonadotrophin is the actual ligand of the LH receptor (LHR) of the marmoset monkey that naturally lacks exon 10, we identified and characterised the genomic organisation of the mLH gene and its expression. Intergenic PCR amplification of the region encompassing the mLH and the mCG genes revealed that, surprisingly, mCG is located 20 kbp upstream of the LH gene, whereas in other species the intergenic distance is approximately 2-3 kbp. Sequence analysis of the mLH coding region showed 70% identity to mCG and 90% identity to human LH at the amino acid level. Both gonadotrophin subunits are present at the genomic level, but RT-PCR of pituitary and placental total RNA using specific oligonucleotides for mCG and mLH showed high expression of mCG mRNA in both tissues, whereas LH was expressed neither in the pituitary nor in the placenta. Thus mLH mRNA is lacking in the marmoset pituitary. Immunohistochemistry of marmoset pituitaries showed that mCG was confined to the gonadotrophes, and partly co-localised in cells stained positively for FSH. Western blot analysis confirmed the presence of mCG in the pituitary. Northern blot analysis using mCG as a probe displayed one transcript of 0·7 kb in the pituitary and detected two transcripts of 1·1 kb and 2 kb in the marmoset placenta. Our results suggest that, in the common marmoset, CG is the only gonadotrophin with luteinising function that is present in the pituitary. We postulate that, owing to an unknown mutational event in evolution, expression of mLH was completely abolished, and CG -which, unlike LH, acts normally even when exon 10 is missing from the LHR -took over its function.

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“…Examination of the CTP sequences of CG␤ subunits from human (4), baboon (bab) (8), marmoset (mar) (9), equine (e) (7), donkey (d) (10), and zebra (z) (11) reveals that in addition to containing Ser/Thr-and Pro-rich regions, a cluster of serines located 4 -7 residues downstream from the conserved Cys 110 residue is a sequence signature (Fig. 1B).…”

mentioning

confidence: 99%

The LHβ Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla

Nakav

Jablonka‐Shariff

Kaner

et al. 2005

Journal of Biological Chemistry

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The expression of a previously untranslated carboxylterminal sequence is associated with the ancestral lutropin (LH) ␤ to the ␤-subunit gene evolution of choriogonadotropins (CG). The peptide extension (denoted as CTP) is rich in mucin-type O-glycans and confers new hormonal properties on CG relative to the LH. Although the LH␤ gene is conserved among mammals and only a few frameshift mutations account for the extension, it is merely seen in primates and equids. Bioinformatics identified a CTP-like sequence that is encrypted in the LH␤ gene of several mammalian species but not in birds, amphibians, or fish. We then examined whether or not decoding of the cryptic CTP in the bovine LH␤ gene (boCTP) would be sufficient to generate the LH␤ species of a ruminant with properties typical to the CG␤ subunit. The mutated bovine LH␤-boCTP subunit was expressed and N-glycosylated in transfected Chinese hamster ovary cells. However, unlike human (h) CG␤ CTP, the cryptic boCTP was devoid of mucin O-glycans. This deficiency was further confirmed when the boCTP domain was substituted for the natural CTP in the human CG␤ subunit. Moreover, when expressed in polarized Madin-Darby canine kidney cells, this hCG␤-boCTP chimera was secreted basolaterally rather than from the apical compartment, which is the route of the wild type hCG␤ subunit, a sorting function attributed to the Oglycans attached to the CTP. This result shows that the cryptic peptide does not orientate CG to the apical face of the placenta, to the maternal circulation as seen in primates. The absence of this function, which distinguishes CG from LH, provides an explanation as to why the LH␤ to CG␤ evolution did not occur in ruminants. We propose that in primates and equids, further natural mutations in the progenitor LH␤ gene resulted in the efficient O-glycosylation of the CTP, thus favoring the retention of an elongated reading frame.The family of glycoprotein hormones includes lutropin (LH), 1 follitropin, and thyrotropin, as expressed by the pituitary, and chorionic gonadotropin (CG), which is produced by the placenta of primates and equids (1). Each hormone is a noncovalent heterodimer composed of a common ␣-subunit and a unique ␤-subunit that confers receptor specificity. The ␤-subunits have substantial sequence similarities, including conserved location of cysteine residues that suggests an origin from a common ancestral gene (2). The human (h) CG␤ genes have evolved from an ancestral LH␤ gene by frameshift mutations that resulted in a readthrough into a previously untranslated region and the extension of the reading frame (3, 4) (Fig. 1A). As a result, a short carboxyl-terminal sequence of hLH␤ is replaced by a longer carboxyl-terminal peptide (CTP) in hCG␤ (3-6). In the equine (e), both the placental CG␤ and pituitary LH␤ subunits are products of the same gene (eLH/CG␤) and contain a CTP that is presumed to have evolved by a distinct mechanism (7) (for further explanations see "Results"). Except for primates and equids, no other identified animal species b...

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Luteinizing Hormone/Chorionic Gonadotropin Bioactivity in the Common Marmoset (Callithrixjacchus) is Due to a Chorionic Gonadotropin Molecule with a Structure Intermediate between Human Chorionic Gonadotropin and Human Luteinizing Hormone

Cited by 34 publications

References 35 publications

Molecular cloning of pituitary glycoprotein α-subunit and follicle stimulating hormone and chorionic gonadotropin β-subunits from New World squirrel monkey and owl monkey

Molecular cloning of pituitary glycoprotein α-subunit and follicle stimulating hormone and chorionic gonadotropin β-subunits from New World squirrel monkey and owl monkey

Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus)

The LHβ Gene of Several Mammals Embeds a Carboxyl-terminal Peptide-like Sequence Revealing a Critical Role for Mucin Oligosaccharides in the Evolution of Lutropin to Chorionic Gonadotropin in the Animal Phyla

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