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Research Article

Functional New World monkey oxytocin forms elicit an altered signaling profile and promotes parental care in rats

Lucas T. Parreiras-e-Silva, Pedro Vargas-Pinilla, Diego A. Duarte, Dânae Longo, Grace Violeta Espinoza Pardo, Andrea Dulor Finkler, View ORCID ProfileVanessa Rodrigues Paixão-Côrtes, Pâmela Paré, Diego L. Rovaris, Eduardo B. Oliveira, Rafael Andrade Caceres, Gislene L. Gonçalves, Michel Bouvier, Francisco M. Salzano, Aldo B. Lucion, Claudio M. Costa-Neto, and Maria Cátira Bortolini
  1. aDepartamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14040-900 Ribeirão Preto, São Paulo, Brazil;
  2. bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
  3. cInstituto Federal Farroupilha, 97555-000 Alegrete, Rio Grande do Sul, Brazil;
  4. dDepartamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90050-170 Porto Alegre, Rio Grande do Sul, Brazil;
  5. eDepartamento de Biologia Geral, Instituto de Biologia, Universidade Federal da Bahia, 40170-290 Salvador, Bahia, Brazil;
  6. fUniversidade Federal de Ciências da Saúde de Porto Alegre, 90050-170 Porto Alegre, Rio Grande do Sul, Brazil;
  7. gDepartment of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada;
  8. hInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada

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PNAS August 22, 2017 114 (34) 9044-9049; first published August 7, 2017; https://doi.org/10.1073/pnas.1711687114
Lucas T. Parreiras-e-Silva
aDepartamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14040-900 Ribeirão Preto, São Paulo, Brazil;
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Pedro Vargas-Pinilla
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
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Diego A. Duarte
aDepartamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14040-900 Ribeirão Preto, São Paulo, Brazil;
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Dânae Longo
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
cInstituto Federal Farroupilha, 97555-000 Alegrete, Rio Grande do Sul, Brazil;
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Grace Violeta Espinoza Pardo
dDepartamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90050-170 Porto Alegre, Rio Grande do Sul, Brazil;
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Andrea Dulor Finkler
dDepartamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90050-170 Porto Alegre, Rio Grande do Sul, Brazil;
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Vanessa Rodrigues Paixão-Côrtes
eDepartamento de Biologia Geral, Instituto de Biologia, Universidade Federal da Bahia, 40170-290 Salvador, Bahia, Brazil;
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  • ORCID record for Vanessa Rodrigues Paixão-Côrtes
Pâmela Paré
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
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Diego L. Rovaris
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
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Eduardo B. Oliveira
aDepartamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14040-900 Ribeirão Preto, São Paulo, Brazil;
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Rafael Andrade Caceres
fUniversidade Federal de Ciências da Saúde de Porto Alegre, 90050-170 Porto Alegre, Rio Grande do Sul, Brazil;
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Gislene L. Gonçalves
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
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Michel Bouvier
gDepartment of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada;
hInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada
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Francisco M. Salzano
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
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  • For correspondence: francisco.salzano@ufrgs.br alucion@ufrgs.br claudio@fmrp.usp.br maria.bortolini@ufrgs.br
Aldo B. Lucion
dDepartamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90050-170 Porto Alegre, Rio Grande do Sul, Brazil;
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  • For correspondence: francisco.salzano@ufrgs.br alucion@ufrgs.br claudio@fmrp.usp.br maria.bortolini@ufrgs.br
Claudio M. Costa-Neto
aDepartamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14040-900 Ribeirão Preto, São Paulo, Brazil;
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  • For correspondence: francisco.salzano@ufrgs.br alucion@ufrgs.br claudio@fmrp.usp.br maria.bortolini@ufrgs.br
Maria Cátira Bortolini
bDepartamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, Rio Grande do Sul, Brazil;
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  • For correspondence: francisco.salzano@ufrgs.br alucion@ufrgs.br claudio@fmrp.usp.br maria.bortolini@ufrgs.br
  1. Contributed by Francisco M. Salzano, July 12, 2017 (sent for review December 1, 2016; reviewed by Ali Salahpour and Froylán Vargas-Martínez)

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Significance

Several forms of the oxytocin neurohormone have been found in New World monkeys (NWMs). Previous research has suggested an association between these forms and behaviors typical of this primate branch, including paternal care and monogamy. Our study provides genetic, pharmacological, behavioral, and in silico evidence supporting this connection. Rats treated intranasally with two NWM oxytocin variants showed an increase in some parental care behaviors. The same two variants were found to elicit different cell-signaling profiles in cell-based assays compared with ancestral oxytocin. Our findings highlight how mutations in the OXT DNA sequence coding for a nonapeptide result in distinct signaling profiles that may be linked to the emergence of novel adaptive traits, in this case, paternal care and monogamy.

Abstract

The neurohormone oxytocin is a key player in the modulation of reproductive and social behavioral traits, such as parental care. Recently, a correlation between different forms of oxytocin and behavioral phenotypes has been described in the New World Monkeys (NWMs). Here, we demonstrate that, compared with the Leu8OXT found in most placental mammals, the Cebidae Pro8OXT and Saguinus Val3Pro8OXT taxon-specific variants act as equi-efficacious agonists for the Gq-dependent pathway but are weaker agonists for the β-arrestin engagement and subsequent endocytosis toward the oxytocin receptor (OXTR). Upon interaction with the AVPR1a, Pro8OXT and the common Leu8OXT yielded similar signaling profiles, being equally efficacious on Gq and β-arrestin, while Val3Pro8OXT showed reduced relative efficacy toward β-arrestin. Intranasal treatment with either of the variants increased maternal behavior and also promoted unusual paternal care in rats, as measured by pup-retrieval tests. We therefore suggest that Val3Pro8OXT and Pro8OXT are functional variants, which might have been evolutionarily co-opted as an essential part of the adaptive genetic repertoire that allowed the emergence of taxon-specific complex social behaviors, such as intense parental care in the Cebidae and the genus Saguinus.

  • paternal care
  • biased agonism
  • primates
  • oxytocin variants
  • social behaviors

Footnotes

  • ↵1L.T.P.-e.-S., P.V.-P., and D.A.D. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: francisco.salzano{at}ufrgs.br, alucion{at}ufrgs.br, claudio{at}fmrp.usp.br, or maria.bortolini{at}ufrgs.br.
  • Author contributions: L.T.P.-e.-S., P.V.-P., D.A.D., D.L., A.B.L., C.M.C.-N., and M.C.B. designed research; L.T.P.-e.-S., P.V.-P., D.A.D., D.L., G.V.E.P., A.D.F., P.P., and G.L.G. performed research; E.B.O., R.A.C., M.B., A.B.L., C.M.C.-N., and M.C.B. contributed new reagents/analytic tools; L.T.P.-e.-S., P.V.-P., D.A.D., D.L., V.R.P.-C., D.L.R., M.B., A.B.L., C.M.C.-N., and M.C.B. analyzed data; and L.T.P.-e.-S., P.V.-P., D.A.D., D.L., R.A.C., M.B., F.M.S., A.B.L., C.M.C.-N., and M.C.B. wrote the paper.

  • Reviewers: A.S., University of Toronto; and F.V.-M., Cinvestav l.P.N.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1711687114/-/DCSupplemental.

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New World monkey OXT forms are Gq-biased agonists
Lucas T. Parreiras-e-Silva, Pedro Vargas-Pinilla, Diego A. Duarte, Dânae Longo, Grace Violeta Espinoza Pardo, Andrea Dulor Finkler, Vanessa Rodrigues Paixão-Côrtes, Pâmela Paré, Diego L. Rovaris, Eduardo B. Oliveira, Rafael Andrade Caceres, Gislene L. Gonçalves, Michel Bouvier, Francisco M. Salzano, Aldo B. Lucion, Claudio M. Costa-Neto, Maria Cátira Bortolini
Proceedings of the National Academy of Sciences Aug 2017, 114 (34) 9044-9049; DOI: 10.1073/pnas.1711687114

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New World monkey OXT forms are Gq-biased agonists
Lucas T. Parreiras-e-Silva, Pedro Vargas-Pinilla, Diego A. Duarte, Dânae Longo, Grace Violeta Espinoza Pardo, Andrea Dulor Finkler, Vanessa Rodrigues Paixão-Côrtes, Pâmela Paré, Diego L. Rovaris, Eduardo B. Oliveira, Rafael Andrade Caceres, Gislene L. Gonçalves, Michel Bouvier, Francisco M. Salzano, Aldo B. Lucion, Claudio M. Costa-Neto, Maria Cátira Bortolini
Proceedings of the National Academy of Sciences Aug 2017, 114 (34) 9044-9049; DOI: 10.1073/pnas.1711687114
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