Research ReportModulation of estrogen receptors during development inhibits neurogenesis of precursors to GnRH-1 neurones: In vitro studies with explants of ovine olfactory placode
Introduction
Gonadotropin releasing hormone-1 (GnRH-1) is a decapeptide neurohormone that controls different aspects of vertebrate reproductive life (Ordog et al., 1997). At the end of gestation and/or during perinatal life, GnRH-1 is secreted in a pulsatile fashion, and stimulates the production of steroid hormones by the fetal and neonatal gonads contributing to the sexual differentiation of the external genitalia and the central nervous system. The secretion of GnRH-1 is strongly suppressed during infancy before being reactivated at the time of puberty to ensure normal gametogenesis and endocrine function of the gonads, the secretion of GnRH-1 by GnRH-1 neurons then continues during adult reproductive life and is subject to internal (steroid feedback, regulatory peptides, etc) and external regulation (photoperiod, nutritional status, social cues). Despite its functional importance, GnRH-1 is synthesized and secreted by a small number of neurons (800 in the mouse (Hoffman and Finch, 1986, Wray et al., 1989), 3000 in the sheep (Caldani et al., 1988) scattered between the preoptic area (POA) and the medial basal hypothalamus (MBH). Another characteristic of GnRH-1 neurons is their embryological origin: as far as we know, they are the only neurons in the central nervous system (CNS) originating outside the brain (Wray et al., 1989, Schwanzel-Fukuda and Pfaff, 1989). Their precursors appear in the medial part of the olfactory placode and migrate along the main and accessory olfactory nerves towards the cribiform plate. In contrast to olfactory projections, which project to the main and accessory olfactory bulbs, precursors of GnRH-1 neurons continue their progression along the terminal nerves between the telencephalic vesicles towards the POA and the anterior hypothalamus, their final destination. This sequence of events has now been well documented in various species. In chicken (Mulrenin et al., 1999) and sheep (Bruneau et al., 2003), the GnRH-1 neuron precursors are located in the medial olfactory region and their neurogenesis is prolonged compared to mice (Wray et al., 1989). Whereas numerous studies have explored the role of gonadal or synthetic steroids on the regulation of GnRH-1 neurons in prepubertal or adult animals (see for reviews (Foster et al., 2006, Tena-Sempere, 2006, Gamba and Pralong, 2006, Clarkson and Herbison, 2006), few studies have focused on the role of these steroids during the ontogenesis of the GnRH-1 neurons.
Thus, in the present study we examined the effects of the natural estrogen receptor ligands: 17-β-estradiol (E 17β), 17α-estradiol (E 17α) and the synthetic estrogen receptor ligand: tamoxifen (Tx) on early development of GnRH-1 neurons in a model of ovine olfactory placode explants maintained in primary culture.
Section snippets
Neuronal morphology
All treatments stimulated neurite length with a greater effect found in the E17β-treated group: 57.24 ± 6.97 μm (Mean ± sem, n = 6) versus 38.46 ± 1.59 μm (Mean ± sem, n = 6) for the control group which corresponds to a 34% increase. The mean neurite length was also increased in the E17α and Tx treated groups with mean neurite lengths of 56.42 ± 5.38 (Mean ± sem, n = 4) and 53.59 ± 5.54 μm (Mean ± sem, n = 8) respectively (Fig. 1). This difference was statistically significant (ANOVA, Newman–Keuls post hoc test p ≤
Discussion
The aim of this study was to evaluate the effect of ER-modulation of GnRH-1 neurons in early development. Using an in vitro model of primary culture of GnRH-1 neurons derived from the olfactory placode of ovine embryos we have shown that ligands of estradiol receptors such as tamoxifen and 17-α-estradiol decreased neurogenesis of the precursors of GnRH-1 neurons in a drastic manner whereas supplementation with 17-β-estradiol had no statistically significant effect on the neurogenesis of GnRH-1
Experimental procedures
A total of 53 explants were tested: 17 in the control group (C), 13 in the17β-Estradiol-treated group (E 17β), 10 in the17α-Estradiol-treated group (E 17α) and 13 in the tamoxifen-treated group (Tx).
Acknowledgments
Thanks to Dr Corinne Cotinot who provided us SRY-probes. Thanks to the shepherds at the Experimental Unit (UPEA) in Nouzilly who looked after the animals.
References (64)
- et al.
beta-estradiol influences differentiation of hippocampal neurons in vitro through an estrogen receptor-mediated process
Neuroscience
(2003) - et al.
Ontogeny of the neurosteroid enzyme Cyp7b in the mouse
Mol. Cell. Endocrinol.
(2001) - et al.
Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation
Mol. Cell. Neurosci.
(2002) - et al.
Independent masculinization of neuroendocrine systems by intracerebral implants of testosterone or estradiol in the neonatal female rat.
Brain Res.
(1978) - et al.
Development of GABA and glutamate signaling at the GnRH neuron in relation to puberty
Mol. Cell. Endocrinol.
(2006) - et al.
Interaction of insulin-like growth factor-I and estradiol signaling pathways on hypothalamic neuronal differentiation
Neuroscience
(1996) - et al.
Programming of GnRH feedback controls timing puberty and adult reproductive activity
Mol. Cell. Endocrinol.
(2006) - et al.
LHRH cells migarte on peripherin sensitive fibers in embryonic olfactory explant cultures: an in vitro model for neurophilic neuronal migration
Dev. Biol.
(1994) - et al.
Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin
Mol. Cell. Endocrinol.
(2006) - et al.
The effects of estradiol on gonadotropin-releasing hormone neurons in the developing mouse brain
Gen. Comp. Endocrinol.
(1998)
Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V)
Brain Res. Rev.
New evidence for estrogen receptors in gonadotropin-releasing hormone neurons
Front. Neuroendocrinol.
LHRH neurons in the female C57BL/6J mouse brain during reproductive aging: no loss up to middle age
Neurobiol. Aging
The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems
Front. Neuroendocrinol.
17b-estradiol enhances neuronal differentiation of mouse embryonic stem cells.
FEBS Lett.
The ins and outs of GPR30: a transmembrane estrogen receptor
J. Steroid Biochem. Mol. Biol.
Neurosteroid synthesis in the hippocampus: role in synaptic plasticity
Neuroscience
Spatiotemporal cell expression of luteinizing hormone-releasing hormone in the prenatal mouse: evidence for an embryonic origin in the olfactory placode.
Dev. Brain Res.
Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep
Neuroscience
Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity
Exp. Neurol.
Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signaling.
J. Neurosci. Res.
Serotonin mediates estrogen stimulation of cell proliferation in the adult denate gyrus.
Eur. J. Neurosci.
Neuroanatomical organization of gonadotropin-releasing hormone neurons during the oestrus cycle in the ewe.
BMC Neurosci.
Prolonged neurogenesis during early development of gonadotropin-releasing hormone neurones in sheep (Ovis aries): in vivo and in vitro studies
Neuroendocrinology
LHRH-immunoreactive structures in the sheep brain
Histochemistry
Evidence that the mediobasal hypothalamus is the primary site of action of estradiol in inducing the preovulatory gonadotropin releasing hormone surge in the ewe
Endocrinology
Disordered follicle development in ovaries of prenatally androgenized ewes
J. Endocrinol.
Sexual differentiation of the neuroendocrine control of gonadotrophin secretion: concepts derived from sheep models
Reproduction
Nonclassical estrogen receptor alpha signaling mediates negative feedback in the female mouse reproductive axis
Proc. Natl. Acad. Sci. U. S. A.
Importance of perinatal testosterone in sexual differentiation in the male rat
J. Endocrinol.
Sexual differentiation of the surge mode of gonadotropin secretion: prenatal androgens abolish the gonadotropin-releasing hormone surge in the sheep
J. Neuroendocrinol.
Stress in pregnancy activates neurosteroid production in the fetal brain
Neuroendocrinology
Cited by (7)
Evidence of reproductive disruption associated with neuroendocrine changes induced by UV-B filters, phtalates and nonylphenol during sexual maturation in rats of both gender
2013, ToxicologyCitation Excerpt :On the other hand, testosterone produces a tonic inhibitory feedback on neuroendocrine system in males (Mooradian et al., 1987). It is important to underline that GnRH neurons could be directly involved in responding to estrogens (Matagne et al., 2003) from early development stage, when 17 β estradiol (100 nM) stimulates the neurogenesis of precursors to GnRH neurons in the olfatory placode (Agça et al., 2008). In adulthood these estrogenic effects may become by indirect mechanism, involving other estrogen responsive cells.
Maternal exposure to 17-alpha-ethinylestradiol alters embryonic development of GnRH-1 neurons in mouse
2012, Brain ResearchCitation Excerpt :They enter the brain under the olfactory bulbs and then disperse into their definitive location (Jasoni et al., 2009; Wray, 2002). Studies performed in vitro have shown that neural precursors of GnRH-1 neurons are sensitive to the presence of estrogen in their microenvironment during early development (Agça et al., 2008). EE2 is the main component of contraceptive pills and hormonal substitutive treatments (Brincat et al., 2003).
Neuroendocrine disruption of pubertal timing and interactions between homeostasis of reproduction and energy balance
2010, Molecular and Cellular EndocrinologyEnhanced co-expression of β-tubulin III and choline acetyltransferase in neurons from mouse embryonic stem cells promoted by icaritin in an estrogen receptor-independent manner
2009, Chemico-Biological InteractionsCitation Excerpt :A neuronal differentiation stimulatory phenotype was shown by the treatment of some prenylflavonoids, such as icaritin [7] and isobavachin (data unshowed). Icaritin was also demonstrated to be a prenylflavonoid estrogen receptor (ER) modulator and possess neuroprotective effects in estrogen-like characteristics [8,9], in which the estrogen receptor signaling [10,11] and ERK-MAPK signaling pathways were involved [3]. Considering 17β-estradiol also possessed the neurogenesis stimulatory effects [10–12] and p38MAPK constituted as an early switch of committing ES cells into either neurogenesis (p38 off) or cardiomyogenesis (p38 on) [13], we presumed that icaritin might exert the neuronal differentiation stimulatory effects via extracellular environment modulation.
Tamoxifen Treatment in the Neonatal Period Affects Glucose Homeostasis in Adult Mice in a Sex-Dependent Manner
2021, Endocrinology (United States)