Ma YJ, Junier M-P, Costa ME, Ojeda STransforming growth factor- gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation. Neuron 9:657-670

Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton 97006.
Neuron (Impact Factor: 15.05). 11/1992; 9(4):657-70. DOI: 10.1016/0896-6273(92)90029-D
Source: PubMed


Hypothalamic injury causes female sexual precocity by activating luteinizing hormone-releasing hormone (LHRH) neurons, which control sexual development. Transforming growth factor-alpha (TGF-alpha) has been implicated in this process, but its involvement in normal sexual maturation is unknown. The present study addresses this issue. TGF-alpha mRNA and protein were found mostly in astroglia, in regions of the hypothalamus concerned with LHRH control. Hypothalamic TGF-alpha mRNA levels increased at times when secretion of pituitary gonadotropins--an LHRH-dependent event--was elevated, particularly at the time of puberty. Gonadal steroids involved in the control of LHRH secretion increased TGF-alpha mRNA levels. Blockade of TGF-alpha action in the median eminence, a site of glial-LHRH nerve terminal association, delayed puberty. These results suggest that TGF-alpha of glial origin is a component of the developmental program by which the brain controls mammalian sexual maturation.

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    • "Importantly, gonadal steroids have been found to induce dramatic increases in the expression levels of the erbB receptors and their ligands within the hypothalamus at puberty; no such changes are seen in the cortex or other brain regions unrelated to reproductive control (Ma et al., 1992, 1994a, 1999). The pharmacological or genetic inhibition of erbB1, erbB2, and/or erbB4 receptors delays the onset of puberty (Ma et al., 1992; Apostolakis et al., 2000; Prevot et al., 2003b, 2005) and alters adult reproductive function in rodents (Prevot et al., 2005). In vitro studies using either hypothalamic explants or primary cultures of hypothalamic astrocytes with a GnRH-producing neuronal cell line have shown that erbB receptor ligands can stimulate GnRH release from the explants or neuronal cells, but do so indirectly, by inducing astrocytes to secrete PGE 2 (Ojeda et al., 1990; Ma et al., 1997, 1999; Prevot et al., 2003b, 2005). "
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    ABSTRACT: Over the past four decades it has become clear that prostaglandin E(2) (PGE(2)), a phospholipid-derived signaling molecule, plays a fundamental role in modulating the gonadotropin-releasing hormone (GnRH) neuroendocrine system and in shaping the hypothalamus. In this review, after a brief historical overview, we highlight studies revealing that PGE(2) released by glial cells such as astrocytes and tanycytes is intimately involved in the active control of GnRH neuronal activity and neurosecretion. Recent evidence suggests that hypothalamic astrocytes surrounding GnRH neuronal cell bodies may respond to neuronal activity with an activation of the erbB receptor tyrosine kinase signaling, triggering the release of PGE(2) as a chemical transmitter from the glia themselves, and, in turn, leading to the feedback regulation of GnRH neuronal activity. At the GnRH neurohemal junction, in the median eminence of the hypothalamus, PGE(2) is released by tanycytes in response to cell-cell signaling initiated by glial cells and vascular endothelial cells. Upon its release, PGE(2) causes the retraction of the tanycyte end-feet enwrapping the GnRH nerve terminals, enabling them to approach the adjacent pericapillary space and thus likely facilitating neurohormone diffusion from these nerve terminals into the pituitary portal blood. In view of these new insights, we suggest that synaptically associated astrocytes and perijunctional tanycytes are integral modulatory elements of GnRH neuronal function at the cell soma/dendrite and nerve terminal levels, respectively.
    Frontiers in Endocrinology 12/2011; 2:91. DOI:10.3389/fendo.2011.00091
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    • "While both can stimulate LHRH release [9], TGFα has been shown to play a more pivotal role in the regulation of LHRH neuronal function during puberty in rodents [13,15] and primates [16]. TGFα mRNA and protein are highly expressed in glial cells and tanycytes in the MBH, their expressions increase significantly around the time of puberty [39], and pharmacological blockade of the erbB 1 receptor [40] targeted to the MBH delays puberty [39]. Additionally, sexual maturation induced by hypothalamic lesions is associated with activation of TGFα expression in glial cells [41,42], and the effect of this lesion on puberty is blocked by using a selective inhibitor (RG-50864) of TGFα/EGF receptor tyrosine kinase activity [41]. "
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    ABSTRACT: Mammalian puberty requires complex interactions between glial and neuronal regulatory systems within the hypothalamus that results in the timely increase in the secretion of luteinizing hormone releasing hormone (LHRH). Assessing the molecules required for the development of coordinated communication networks between glia and LHRH neuron terminals in the basal hypothalamus, as well as identifying substances capable of affecting cell-cell communication are important. One such pathway involves growth factors of the epidermal growth factor (EGF) family that bind to specific erbB receptors. Activation of this receptor results in the release of prostaglandin-E(2) (PGE(2)) from adjacent glial cells, which then acts on the nearby LHRH nerve terminals to elicit release of the peptide. Another pathway involves novel genes which synthesize adhesion/signaling proteins responsible for the structural integrity of bi-directional glial-neuronal communication. In this review, we will discuss the influence of these glial-neuronal communication pathways on the prepubertal LHRH secretory system, and furthermore, discuss the actions and interactions of alcohol on these two signaling processes.
    International Journal of Environmental Research and Public Health 07/2011; 8(7):2876-94. DOI:10.3390/ijerph8072894 · 2.06 Impact Factor
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    • "The cell adhesiveness component also promotes a more secure proximity for glial-derived secretions to bind to their receptors on the LHRH nerve terminals. Insulin-like growth factor 1 (IGF-1), transforming growth factor alpha (TGFα) and epidermal growth factor (EGF) are all puberty-related peptides that are synthesized and secreted from glia (Duenas et al., 1994; Ma et al., 1992; Ojeda et al., 2000).Once released, these peptides bind to their receptors on adjacent glial cells, thereby inducing the synthesis and secretion of PGE 2 . The PGE 2 then binds to the PGE 2 -receptor on the nearby LHRH nerve terminals, facilitating the release of this peptide that controls the timing of puberty. "
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    ABSTRACT: Hypothalamic glial-neuronal communications are important for the activation of luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. As we have shown that alcohol (ALC) diminishes prepubertal LHRH secretion and delays puberty, we first assessed the effects of short-term ALC administration on the basal expression of a specific gene family involved in glial-neuronal communications. Second, as insulin-like growth factor-1 (IGF-1) is a critical regulator of LHRH secretion and the pubertal process, we then assessed whether IGF-1 could induce the expression of these signaling genes and determine whether ALC can block this affect. Immature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Control animals received either the companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Medial basal hypothalamic (MBH) tissues were obtained for gene and protein analyses of glial receptor protein tyrosine phosphatase-β (RPTPβ) and the 2 neuronal components, contactin and contactin-associated protein 1 (Caspr1). In the second experiment, IGF-1 was administered into the third ventricle (3V) and the MBH removed 6 hours after peptide delivery, and the above-mentioned 3 genes were analyzed by real-time PCR. To determine whether this action was affected by ALC, immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0900 hours. At 1030 hours, the ALC and control groups were subdivided such that half of the animals were injected into the 3V with IGF-1 and the other half with an equal volume of saline. Rats were killed 6 hours after the IGF-1 injection and MBHs collected. Real-time PCR showed that when compared with control animals, ALC caused a marked decrease (p < 0.001) in the basal expression of the RPTPβ gene, but did not affect the expression of either contactin or Caspr1. Likewise, analysis by Western blotting demonstrated that ALC caused suppressed (p < 0.001) levels of the RPTPβ protein, with the expressions of both contactin and Caspr1 proteins being unaltered. In the second experiment, results showed that only the RPTPβ gene was stimulated (p < 0.05) by IGF-1 in the MBH 6 hours after peptide delivery. Assessments revealed that the IGF-1 induced increase (p < 0.01) in the expression of the RPTPβ gene was blocked by the presence of ALC. Prepubertal ALC exposure is capable of interfering with hypothalamic glial-neuronal communications by suppressing the synthesis of the glial product, RPTPβ, which is required for binding to the contactin-Caspr1 complex on LHRH neuronal terminals, thus suggesting that this action of ALC contributes to its detrimental effects on the pubertal process.
    Alcoholism Clinical and Experimental Research 05/2011; 35(10):1812-21. DOI:10.1111/j.1530-0277.2011.01525.x · 3.21 Impact Factor
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