TRANSFORMING GROWTH FACTOR-ALPHA CONTRIBUTES TO THE MECHANISM BY WHICH HYPOTHALAMIC INJURY INDUCES PRECOCIOUS PUBERTY
TRANSFORMING GROWTH FACTOR-ALPHA CONTRIBUTES TO THE MECHANISM BY WHICH HYPOTHALAMIC INJURY INDUCES PRECOCIOUS PUBERTY
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DOI：
10.1073/pnas.88.21.9743
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发表时间：
1991-11-01
影响因子：
11.1
通讯作者：
OJEDA, SR
中科院分区：
文献类型：
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作者：
JUNIER, MP;MA, YJ;OJEDA, SR
人们早就知道下丘脑的病变会导致女性性早熟。虽然黄体生成素释放激素（LHRH）（控制性发育的神经激素）的产生增加似乎介导了这些病变引起的青春期提前，但人们对下丘脑损伤激活 LHRH 分泌的机制知之甚少。由于脑损伤会导致损伤区域神经营养/促有丝分裂活性的积累，我们测试了以下假设：转化生长因子-α (TGF-α)（一种最近显示可刺激 LHRH 释放的促有丝分裂多肽）是响应下丘脑损伤而产生的，并介导损伤对青春期的影响。 22日龄雌性大鼠视前区-下丘脑前区（POA-AHA）射频损伤术后7天内出现性早熟。 RNA 印迹杂交显示，在损伤诱导的青春期之前，POA-AHA 中 TGF-α mRNA 水平增加。在完整和受损的下丘脑中都检测不到表皮生长因子 (EGF) mRNA。通过 RNase 保护测定定量，接近青春期的病变动物的 TGF-α mRNA 水平比年龄匹配的对照高 3.5 倍。利用单染色和双染色程序的免疫组织化学研究证明，病变部位周围的反应性星形胶质细胞中存在 TGF-α 前体样免疫反应性。杂交组织化学显示同一区域的细胞中 TGF-α mRNA 表达增加，进一步表明反应性星形胶质细胞是 TGF-α 合成的位点。 TGF-α 的作用是通过其与 EGF 受体的相互作用介导的。在损伤部位持续输注 RG-50864（一种 EGF 受体激酶活性抑制剂）可阻止损伤引起的青春期提前。这些结果表明，TGF-α 通过 EGF 样受体发挥作用，有助于加速由下丘脑前部病变引起的青春期。他们还表明，神经胶质细胞中TGF-α基因表达的激活是下丘脑对损伤反应的一个组成部分。
It has long been known that lesions of the hypothalamus lead to female sexual precocity. While an increased production of luteinizing hormone-releasing hormone (LHRH), the neurohormone that controls sexual development, appears to mediate the advancement of puberty induced by these lesions, little is known about the mechanism(s) by which hypothalamic injury activates LHRH secretion. Since brain lesions result in accumulation of neurotrophic/mitogenic activities in the injured area, we tested the hypothesis that transforming growth factor-alpha (TGF-alpha), a mitogenic polypeptide recently shown to stimulate LHRH release, is produced in response to hypothalamic injury and mediates the effect of the lesion on puberty. Radiofrequency lesions of the preoptic area-anterior hypothalamic area (POA-AHA) of 22-day-old female rats resulted in precocious puberty within 7 days after the operation. RNA blot hybridization revealed that lesion-induced puberty was preceded by an increase in TGF-alpha mRNA levels in the POA-AHA. Epidermal growth factor (EGF) mRNA was undetectable in both intact and lesioned hypothalami. TGF-alpha mRNA levels, quantitated by RNase protection assays, were 3.5-fold greater in lesioned animals approaching puberty than in age-matched controls. Immunohistochemical studies, utilizing single- and double-staining procedures, demonstrated the presence of TGF-alpha precursor-like immunoreactivity in reactive astrocytes surrounding the lesion site. Hybridization histochemistry showed increased TGF-alpha mRNA expression in cells of the same area, further implicating reactive astrocytes as a site of TGF-alpha synthesis. The actions of TGF-alpha are mediated by its interaction with EGF receptors. Continuous infusion of RG-50864, an inhibitor of EGF receptor kinase activity, at the site of injury prevented the advancement of puberty induced by the lesion. These results suggest that TGF-alpha acting via EGF-like receptors contributes to the acceleration of puberty induced by anterior hypothalamic lesions. They also indicate that activation of TGF-alpha-gene expression in glial cells is a component of the hypothalamic response to injury.