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Contributed by Francisco M. Salzano, July 12, 2017 (sent for review December 1, 2016; reviewed by Ali Salahpour and Froylán Vargas-Martínez)
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.
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.
New World monkey OXT forms are Gq-biased agonists
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