Original Article

A sexually dimorphic peptidergic system in the lower spinal cord controlling penile function in non-human primates

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Abstract

Study design:

Experimental animal study.

Objectives:

Although a population of gastrin-releasing peptide (GRP) neurons in the lumbar spinal cord has an important role in erection and ejaculation in rats, little information exists on this GRP system in primates. To identify the male-specific GRP system in the primate spinal cord, we studied the lumbosacral cord in macaque monkeys as a non-human primate model.

Setting:

University laboratory in Japan.

Methods:

To determine the gene sequence of GRP precursors, the rhesus macaque monkey genomic sequence data were searched, followed by phylogenetic analysis. Subsequently, immunocytochemical analysis for GRP was performed in the monkey spinal cord.

Results:

We have used bioinformatics to identify the ortholog gene for GRP precursor in macaque monkeys. Phylogenetic analysis suggested that primate prepro-GRP is separated from that of other mammalian species and clustered to an independent branch as primates. Immunocytochemistry for GRP further demonstrated that male-dominant sexual dimorphism was found in the spinal GRP system in monkeys as in rodents.

Conclusion:

We have demonstrated in macaque monkeys that the GRP system in the lower spinal cord shows male-specific dimorphism and may have an important role in penile functions not only in rodents but also in primates.

Sponsorship:

Tissues of Nihonzaru (Japanese macaque monkeys) were provided in part by National Institutes of Natural Sciences (NINS) through the National Bio-Resource Project (NBRP) of the MEXT, Japan. This work was supported in part by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (to KT; 15KK0343, 15J40220 and HS; 15K15202, 15KK0257, 15H05724).

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References

  1. 1.

    , , . Male fertility and sexual function after spinal cord injury. Prog Brain Res 2006; 152: 427–439.

  2. 2.

    . Sexual functioning in the spinal cord injured. Int J Impot Res 1998; 10 (Suppl 2): S128–S130.

  3. 3.

    . Hormonal control of the anatomical specificity of motoneuron-to-muscle innervation in rats. Science 1985; 227: 1357–1359.

  4. 4.

    , , . Sexual differentiation of the vertebrate nervous system. Nat Neurosci 2004; 7: 1034–1039.

  5. 5.

    , , . Androgen action in the brain and spinal cord for the regulation of male sexual behaviors. Curr Opin Pharmacol 2008; 8: 747–751.

  6. 6.

    , . Hormonal control of a developing neuromuscular system. I. Complete demasculinization of the male rat spinal nucleus of the bulbocavernosus using the anti-androgen flutamide. J Neurosci 1983; 3: 417–423.

  7. 7.

    , . Hormonal control of a developing neuromuscular system. II. Sensitive periods for the androgen-induced masculinization of the rat spinal nucleus of the bulbocavernosus. J Neurosci 1983; 3: 424–432.

  8. 8.

    . Brain–spinal cord neural circuits controlling male sexual function and behavior. Neurosci Res 2012; 72: 103–116.

  9. 9.

    . Sexually dimorphic nuclei in the spinal cord control male sexual functions. Front Neurosci 2014; 8: 184.

  10. 10.

    , , , , , et al. Sexually dimorphic gastrin releasing peptide system in the spinal cord controls male reproductive functions. Nat Neurosci 2008; 11: 634–636.

  11. 11.

    , , , , , et al. Androgen regulates development of the sexually dimorphic gastrin-releasing peptide neuron system in the lumbar spinal cord: evidence from a mouse line lacking androgen receptor in the nervous system. Neurosci Lett 2014; 558: 109–114.

  12. 12.

    , , , , , et al. Androgen regulates the sexually dimorphic gastrin-releasing peptide system in the lumbar spinal cord that mediates male sexual function. Endocrinology 2009; 150: 3672–3679.

  13. 13.

    , , , , , et al. Identification of the sexually dimorphic gastrin-releasing peptide system in the lumbosacral spinal cord that controls male reproductive function in the mouse and Asian house musk shrew (Suncus murinus. J Comp Neurol 2017; 525: 1586–1598.

  14. 14.

    , , , , , et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science 2007; 316: 222–234.

  15. 15.

    , , , , , et al. Distribution of gastrin-releasing peptide in the rat trigeminal and spinal somatosensory systems. J Comp Neurol 2014; 522: 1858–1873.

  16. 16.

    , , , , , . Effective synaptome analysis of itch-mediating neurons in the spinal cord: a novel immunohistochemical methodology using high-voltage electron microscopy. Neurosci Lett 2015; 599: 86–91.

  17. 17.

    , , , , , . Three-dimensional visualization of multiple synapses in thick sections using high-voltage electron microscopy in the rat spinal cord. Data Brief 2015; 4: 566–570.

  18. 18.

    , , , , , et al. Perinatal testosterone exposure is critical for the development of the male-specific sexually dimorphic gastrin-releasing peptide system in the lumbosacral spinal cord that mediates erection and ejaculation. Biol Sex Differ 2016; 7: 4.

  19. 19.

    , , , , , et al. Three-dimensional evaluation of the spinal local neural network revealed by the high-voltage electron microscopy: a double immunohistochemical study. Histochem Cell Biol 2012; 138: 693–697.

  20. 20.

    , , , , . Postnatal development of the gastrin-releasing peptide system in the lumbosacral spinal cord controlling male reproductive function in rats. Proc Jpn Acad Ser B Phys Biol Sci 2016; 92: 69–75.

  21. 21.

    , , . The distribution of visceral primary afferents from the pelvic nerve to Lissauer's tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus. J Comp Neurol 1981; 201: 415–440.

  22. 22.

    , , , , , et al. The sacral autonomic outflow is sympathetic. Science 2016; 354: 893–897.

  23. 23.

    , , . Increased expression of neuronal nitric oxide synthase (NOS) in visceral neurons after nerve injury. J Neurosci 1995; 15 (5 Pt 2): 4033–4045.

  24. 24.

    , , . Neuromedin C: a bombesin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun 1984; 119: 14–20.

  25. 25.

    , . The gastrin-releasing peptide receptor (GRPR) in the spinal cord as a novel pharmacological target. Curr Neuropharmacol 2014; 12: 434–443.

  26. 26.

    , , , , . The rat prepro gastrin releasing peptide gene is transcribed from two initiation sites in the brain. Mol Endocrinol 1988; 2: 556–563.

  27. 27.

    , , , , . Cloning and characterization of cDNAs encoding human gastrin-releasing peptide. Proc Natl Acad Sci USA 1984; 81: 5699–5703.

  28. 28.

    , , , , , et al. Structural identification, subcellular localization and secretion of bovine adrenomedullary neuromedin C [GRP-(18-27)]. Peptides 1989; 10: 355–360.

  29. 29.

    , , , , , et al. Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun 1979; 90: 227–233.

  30. 30.

    , , , , , . Gastrin-releasing peptide is produced in the pregnant ovine uterus. Endocrinology 1994; 135: 2440–2445.

  31. 31.

    , , , , , . Amino acid sequences of three bombesin-like peptides from canine intestine extracts. J Biol Chem 1983; 258: 5582–5588.

  32. 32.

    , , . Primary structure and tissue distribution of guinea pig gastrin-releasing peptide. J Neurochem 1987; 49: 1348–1354.

  33. 33.

    , , . High-voltage electron microscopy reveals direct synaptic inputs from a spinal gastrin-releasing peptide system to neurons of the spinal nucleus of bulbocavernosus. Endocrinology 2010; 151: 417–421.

  34. 34.

    , , , . Identification of CNS neurons innervating the levator ani and ventral bulbospongiosus muscles in male rats. J Sex Med 2014; 13: 664–677.

  35. 35.

    , . Sexual dimorphism in human and canine spinal cord: role of early androgen. Proc Natl Acad Sci USA 1986; 83: 7527–7531.

  36. 36.

    , . Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal cord. Science 1980; 210: 564–566.

  37. 37.

    , . The spinal nucleus of the bulbocavernosus: firsts in androgen-dependent neural sex differences. Horm Behav 2008; 53: 596–612.

  38. 38.

    . Notes on the arrangement and function of the cell groups in the sacral region of the spinal cord. J Nerv Mental Dis 1899; 26: 498–504.

  39. 39.

    . Onuf's nucleus of the sacral cord in a South American monkey (Saimiri): its location and bilateral cortical input from area 4. Brain Res 1980; 191: 337–344.

  40. 40.

    , , . Localization of motoneurons innervating perineal muscles: a HRP study in cat. Brain Res 1978; 140: 149–154.

  41. 41.

    , . A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007; 448: 700–703.

  42. 42.

    , , . The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999; 84: 50–56.

  43. 43.

    , . Can lifestyle modification affect men's erectile function? Transl Androl Urol 2016; 5: 187–194.

  44. 44.

    , , , , , et al. Drug Insight: oral phosphodiesterase type 5 inhibitors for erectile dysfunction. Nat Clin Pract Urol 2005; 2: 239–247.

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Acknowledgements

We are grateful to Prof John F Morris (University of Oxford, UK) for his valuable discussion and for reading this manuscript. We thank Prof Mitsuhiro Kawata, Prof Minoru Kimura, Prof Kazuhiro Yagita, Prof Masaki Isoda and Prof Kae Nakamura for providing the fixed monkey spinal cords, their encouragement and/or critical discussion of this study. We thank Dr Yasuhisa Kobayashi, Mr Kazuhiro Saito, Mr Kei Tamura and Mr Toshitsugu Takahashi for their technical assistance. This work was supported in part by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (to KT; 15KK0343, 15J40220 and HS; 15K15202, 15KK0257, 15H05724). Tissues of Nihonzaru (Japanese macaque monkeys) were provided in part by National Institutes of Natural Sciences (NINS) through the National Bio-Resource Project (NBRP) of the MEXT, Japan. KT, TO and KS are supported by Research Fellowships of JSPS for Young Scientists.

Author information

Author notes

    • T Ito
    •  & T Oti

    These authors contributed equally to this work.

Affiliations

  1. Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University, Setouchi, Japan

    • T Ito
    • , T Oti
    • , K Takanami
    • , K Satoh
    • , T Sakamoto
    •  & H Sakamoto
  2. Department of Physiology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    • Y Ueda
  3. Department of Physiology, Kansai Medical University, Hirakata, Japan

    • Y Ueda

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to H Sakamoto.