Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2018

Open Access 01-12-2018 | Research

The relationship between gonadotropin releasing hormone and ovulation inducing factor/nerve growth factor receptors in the hypothalamus of the llama

Authors: Rodrigo A. Carrasco, Jaswant Singh, Gregg P. Adams

Published in: Reproductive Biology and Endocrinology | Issue 1/2018

Login to get access

Abstract

Background

A molecule identical to nerve growth factor, with ovulation-inducing properties has been discovered in the seminal plasma of South American camelids (ovulation-inducing factor/nerve growth factor; OIF/NGF). We hypothesize that the ovulatory effect of OIF/NGF is initiated at the level of the hypothalamus, presumably by GnRH neurons. The objective of the present study was to determine the structural relationship between GnRH neurons and neurons expressing high- and low-affinity receptors for NGF (i.e., TrkA and p75, respectively) in the hypothalamus.

Methods

Mature llamas (n = 4) were euthanized and their hypothalamic tissue was fixed, sectioned, and processed for immunohistochemistry on free-floating sections. Ten equidistant sections per brain were double stained for immunofluorescence detection of TrkA and GnRH, or p75 and GnRH.

Results

Cells immunoreactive to TrkA were detected in most hypothalamic areas, but the majority of cells were detected in the diagonal band of Broca (part of the ventral forebrain) and the supraoptic nuclei and periventricular area. The number of cells immunoreactive to p75 was highest in the diagonal band of Broca and lateral preoptic areas and least in more caudal areas of the hypothalamus (p < 0.05) in a pattern similar to that of TrkA. A low proportion of GnRH neurons were immunoreactive to TrkA (2.5% of total GnRH cells), and no co-localization between GnRH and p75 was detected. GnRH neuron fibers were detected only occasionally in proximity to TrkA immunopositive neurons.

Conclusions

Results do not support the hypothesis that the effect of OIF/NGF is driven by a direct interaction with GnRH neurons, but rather provide rationale for the hypothesis that interneurons exist in the hypothalamus that mediate OIF/NGF-induced ovulation.
Literature
1.
England BG, Foot WC, Matthews DH, Cardozo AG, Riera S. Ovulation and corpus luteum function in the llama (Lama glama). J Endocrinol. 1969;45:505–13.CrossRefPubMed
2.
Fernandez-Baca S, Madden DHL, Novoa C. Effect of different mating stimuli on induction of ovulation in the alpaca. J Reprod Fert. 1970;22:261–7.CrossRef
3.
Adams GP, Ratto MH, Silva ME, Carrasco RA. Ovulation-inducing factor (OIF/NGF) in seminal plasma: a review and update. Reprod Domest Anim. 2016;51(Suppl. 2):4–17.CrossRefPubMed
4.
Adams GP, Ratto MH, Huanca W, Singh J. Ovulation - inducting factor in the seminal plasma of llamas and alpacas. Biol Reprod. 2005;73:452–7.CrossRefPubMed
5.
Berland MA, Ulloa-Leal C, Barria M, Wright H, Dissen GA, Silva ME, Ojeda SR, Ratto MH. Seminal plasma induces ovulation in llamas in the absence of a copulatory stimulus: role of nerve growth factor as an ovulation-inducing factor. Endocrinology. 2016;157:3224–32.CrossRefPubMedPubMedCentral
6.
Ratto MH, Leduc YA, Valderrama XP, Van Straten KE, Delbaere LT, Pierson RA, Adams GP. The nerve of ovulation-inducing factor in semen. Proc Natl Acad Sci U S A. 2012;109:15042–7.CrossRefPubMedPubMedCentral
7.
Ratto MH, Delbaere LT, Leduc YA, Pierson RA, Adams GP. Biochemical isolation and purification of ovulation-inducing factor (OIF) in seminal plasma of llamas. Reprod Biol Endocrinol. 2011;10:9–24.
8.
Tanco VM, Ratto MH, Lazzarotto M, Adams GP. Dose response of female llamas to ovulation-inducing factor (OIF) from seminal plasma. Biol Reprod. 2011;85:452–6.CrossRefPubMed
9.
Silva ME, Smulders JP, Guerra M, Valderrama XP, Letelier C, Adams GP, Ratto MH. Cetrorelix suppresses the preovulatory LH surge and ovulation induced by ovulation-inducing factor (OIF) present in llama seminal plasma. Reprod Biol Endocrinol. 2011;9:74.CrossRefPubMedPubMedCentral
10.
Bogle OA, Ratto MH, Adams GP. Ovulation-inducing factor induces LH secretion from pituitary cells. Anim Reprod Sci. 2012;133:117–22.CrossRefPubMed
11.
Paolicchi F, Urquieta B, Del Valle L, Bustos-Obregon E. Biological activity of the seminal plasma of alpacas: stimulus for the production of LH by pituitary cells. Anim Reprod Sci. 1999;54:203–10.CrossRefPubMed
12.
Adams GP, Sumar J, Ginther OJ. Effects of lactational status and reproductive status on ovarian follicular waves in llamas (Lama glama). J Reprod Fert. 1990;90:535–45.CrossRef
13.
Adams GP. Comparative patterns of follicle development and selection in ruminants. J Reprod Fert. 1999;54:17–32.
14.
Draincourt MA. Regulation of ovarian follicular dynamics in farm animals: implications for manipulation of reproduction. Theriogenology. 2001;55:1211–39.CrossRef
15.
Bravo PW, Stabenfeldt GH, Lasley BL, Fowler ME. The effect of ovarian follicle size on pituitary and ovarian responses to copulation in domesticated South American camelids. Biol Reprod. 1991;45:553–9.CrossRefPubMed
16.
Fair T, Lonergan P. The role of progesterone in oocyte acquisition of developmental competence. Reprod Domest Anim. 2012;47:142–7.CrossRefPubMed
17.
Silva ME, Recabarren MP, Recabarren SE, Adams GP, Ratto MH. Ovarian estradiol modulates the stimulatory effect of ovulation-inducing factor (OIF) on pituitary LH secretion in llamas. Theriogenology. 2012;77:1873–82.CrossRefPubMed
18.
19.
Conner JM, Muir D, Varon S, Hagg T, Manthorpe M. The localization of nerve growth factor-like immunoreactivity in the adult basal forebrain and hippocampal formation. J Comp Neurol. 1992;319:454–62.CrossRefPubMed
20.
Whitemore SR, Ebendal T, Larkfors L, Olson L, Seiger A, Stromberg I, Persson H. Developmental and regional expression of β nerve growth factor messenger RNA and protein in the rat central nervous system. Proc Natl Acad Sci U S A. 1986;83:817–21.CrossRef
21.
Richardson PM, Verge Issa VMK, Riopelle RJ. Distribution of neuronal receptors for nerve growth factor in the rat. J Neurosci. 1986;6:2312–21.CrossRefPubMed
22.
Casaccia-Bonnefil P, Carter BD, Dobrowski RT, Chao MV. Death of oligodendrocites mediated by the interaction of nerve growth factor with its receptor p75. Nature. 1996;383:716–9.CrossRefPubMed
23.
Yoon SO, Casaccia-Bonnefil P, Carter B, Chao MV. Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. Neuroscience. 1998;18:3273–81.CrossRefPubMed
24.
Gibbs RB, Plaff DW. In situ hybridization detection of trka mRNA in brain: distribution, colocalization with p75NGFR and up-regulation by nerve growth factor. J Comp Neurol. 1994;341:324–39.CrossRefPubMed
25.
Sobreviela T, Clary DO, Reichardt LF, Brandabur MM, Kordower JH, Mufson EJ. TrkA-immunoreactive profiles in the central nervous system: Colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltransferase, and serotonin. J Comp Neurol. 1994;350:587–611.CrossRefPubMedPubMedCentral
26.
Ohmichi M, Decker SJ, Pang L, Saltiel AR. Inhibition of the cellular actions of nerve growth factor by staurosporine and k252a from the attenuation of the activity of the trk tyrosine kinase. Biochemistry. 1992;31:4034–9.CrossRefPubMed
27.
Chao MV. Neurotrophins and their receptors: a convergent point for many signaling pathways. Nat Rev Neurosci. 2003;4:299–309.CrossRefPubMed
28.
Clarke IJ, Cummins JT. The relationship between gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology. 1982;111:1737–9.CrossRefPubMed
29.
Hoffman GE, Le WW, Sita LV. The importance of titrating antibodies for immunocytochemical methods. Curr Protoc Neurosci. 2008;2:12.PubMed
30.
Felix B, Léger ME, Fessard DA. Stereotaxic atlas of the pig brain. 1st ed. New York: Elsevier; 1999.
31.
Girgis M, Shih-Cjang W. A new stereotaxic atlas of the rabbit brain. 1st ed. St. Louis: W.H. Green; 1981.
32.
Urban I, Richard P. A stereotaxic atlas of the New Zealand’s rabbit brain. 1st ed. Springfield: Charles C Thomas; 1972.
33.
Fernald RD, White RB. Gonadotropin-releasing hormone genes: phylogeny, structure, and functions. Front Neuroendocrinol. 1999;20:224–40.CrossRefPubMed
34.
Egginger J, Parmentier C, Garrel G, Cohen-Tannougji J, Camus A, Calas A, Hardin-Prouzet H, Grange-Messent V. Direct evidence for the co-expression of URP and GnRH in a sub-population of rat hypothalamic neurons: anatomical and functional correlation. PLoS One. 2011;6:e26611.CrossRefPubMedPubMedCentral
35.
Tillet Y, Tourlet S, Picard S, Sizaret P, Caraty A. Morphofunctional interactions between galanin and GnRH-containing neurones in the diencephalon of the ewe. The effect of oestradiol. J Chem Neuroanat. 2012;43:14–9.CrossRefPubMed
36.
Weskamp G, Reichardt LF. Evidence that biological activity of NGF is mediated through a novel subclass of high affinity receptors. Neuron. 1991;6:649–63.CrossRefPubMed
37.
Lee WS, Smith MS, Hoffman GE. Luteinizing hormone-releasing hormone neurons express fos protein during the proestrus surge of luteinizing hormone. Proc Natl Acad Sci U S A. 1990;87:5163–7.CrossRefPubMedPubMedCentral
38.
Moenter SM, Karsch FJ, Lehman MN. Fos expression during the estradiol-induced gonadotrophin-releasing hormone (GnRH) surge of the ewe: induction in GnRH and other neurons. Endocrinology. 1993;133:896–903.CrossRefPubMed
39.
Wu TJ, Segal AZ, Miller GM, Gibson MJ, Silverman AJ. FOS expression in gonadotropin-releasing hormone neurons: enhancement by steroid treatment and mating. Endocrinology. 1992;131:2045–50.CrossRefPubMed
40.
Herbison A. Physiology of the gonadotropin-releasing hormone neuron network. In: Neil J, editor. Knobil and Neil’s physiology of reproduction. St Louis: Elsevier; 2005. p. 1415–82.
41.
Holtzman DM, Kilbridge J, Li Y, Cunningham ETJ, Lenn NJ, Clary DO, Reichardt LF, Mobley WC. TrkA expression in the CNS: evidence for the existence of several novel NGF-responsive CNS neurons. J Neurosci. 1995;15:1567–76.CrossRefPubMedPubMedCentral
42.
Ferguson IA, Schweitzer JB, Bartlett PF, Johnson EM Jr. Receptor mediated retrograde transport in CNS neurons after intraventricular administration or NGF and growth factors. J Comp Neurol. 1991;313:680–92.CrossRefPubMed
43.
Pan W, Banks WA, Kastin AJ. Permeability of the blood–brain barrier to neurotrophins. Brain Res. 1998;788:87–94.CrossRefPubMed
44.
45.
Rodriguez EM, Blazquez JL, Guerra M. The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides. 2010;31:757–76.CrossRefPubMed
46.
Herde MK, Geist K, Campbell RE, Herbison AE. Gonadotrophin-releasing hormone neurons extend complex highly branched dendritic trees outside the blood brain barrier. Endocrinology. 2012;152:3832–41.CrossRef
47.
Cowley MA, Smart JL, Rubinstein M, Gerdán MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480–4.CrossRefPubMed
48.
Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrel CL. Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into the hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology. 2001;141:1434–41.CrossRef
49.
50.
Timmusk T, Mudó G, Metis M, Belluardo N. Expression of mRNAs for neurotrophin and their receptors in the rat choroid plexus and dura mater. Neuroreport. 1995;15:1997–2000.CrossRef
51.
Ferreira G, Meurisse M, Tillet Y, Lévy F. Distribution and co-localization of choline acetyltransferase and p75 neurotrophin receptors in the sheep basal forebrain: implications for the use of a specific cholinergic immunotoxin. Neuroscience. 2001;104:419–39.CrossRefPubMed
52.
Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, Rasika S, Falluel-morel A, Anouar Y, Dehouck B, Trinquet E, Jockers R, Bouret S, Prevot V. Hypothalamic tanycytes area an ERK- gated conduit for leptin into the brain. Cell Metab. 2014;19:293–301.CrossRefPubMedPubMedCentral
53.
Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol. 2002;67:203–33.CrossRefPubMed
54.
Bronfman FC, Tcherpakov M, Jovin TM, Fainzilber M. Ligand-induced internalization of the p75 neurotrophic receptor: a slow route to the signaling endosome. J Neurosci. 2003;23:3209–20.CrossRefPubMed
55.
Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA. A role for Kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145:4073–7.CrossRefPubMed
56.
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005;102:1761–6.CrossRefPubMedPubMedCentral
57.
Plant TM, Ramaswamy S, Dipietro MJ. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology. 2006;147:1007–13.CrossRefPubMed
58.
Inoue N, Sasaqawa K, Ikai K, Sasaki Y, Tomikawa J, Oishi S, Fuji N, Uenoyama Y, Ohmori Y, Yamamoto N, Hondo E, Maeda K, Tsukamura H. Kisspeptin neurons mediate reflex ovulation in the musk shrew (Suncus murinus). Proc Natl Acad Sci U S A. 2011;108:17527–32.CrossRefPubMedPubMedCentral
59.
El Allali K, El Bousmaki N, Ainani H, Simonneaux V. Effect of Camelid’s seminal plasma ovulation-inducing factor/ β-NGF: a kisspeptin target hypothesis. Front Vet Sci. 2017;4:99.CrossRefPubMedPubMedCentral
60.
Metadata
Title
The relationship between gonadotropin releasing hormone and ovulation inducing factor/nerve growth factor receptors in the hypothalamus of the llama
Authors
Rodrigo A. Carrasco
Jaswant Singh
Gregg P. Adams
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2018
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/s12958-018-0402-6

Other articles of this Issue 1/2018

Reproductive Biology and Endocrinology 1/2018 Go to the issue

Research

Effects of pelvic endometriosis and adenomyosis on ciliary beat frequency and muscular contractions in the human fallopian tube

Review

Human sperm acrosome function assays are predictive of fertilization rate in vitro: a retrospective cohort study and meta-analysis

Research

The preclinical evaluation of immunocontraceptive vaccines based on canine zona pellucida 3 (cZP3) in a mouse model

Review

Radiations and male fertility

Research

An extremely patient-friendly and efficient stimulation protocol for assisted reproductive technology in normal and high responders

Research

The monocyte counts to HDL cholesterol ratio in obese and lean patients with polycystic ovary syndrome