Estrogen induces caspase-dependent cell death during hypothalamic development.
Estrogen induces caspase-dependent cell death during hypothalamic development.
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DOI：
10.1523/jneurosci.0135-09.2009
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发表时间：
2009-08-05
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影响因子：
--
通讯作者：
Simerly RB
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文献类型：
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作者：
Waters EM;Simerly RB
下丘脑视前区（AVPV）前腹侧室周核中多巴胺神经元的性二态性群体在睾酮的影响下出生后发育，睾酮被芳香化为雌激素。有较少的多巴胺能神经元标记的酪氨酸羟化酶（TH）在男性AVPV比女性，性类固醇决定这种性别差异，但细胞死亡的作用，在指定的AVPV多巴胺能神经元的数量是未知的。在体内和体外，AVPV的雌二醇治疗用于操纵TH-免疫反应细胞数。在体外，同时用雌激素受体拮抗剂ICI 182，780治疗拯救了TH-1 R细胞。环孢菌素A，一种依赖于线粒体通透性转换孔开放的细胞死亡抑制剂，也阻止了TH-IR细胞的丢失。在体内，雌二醇增加了AVPV的凋亡概况，TUNEL和Hoechst标记的细胞核的数量。这种增加的凋亡也依赖于雌激素受体α形式的存在。为了测试半胱天冬酶依赖性TH-ir细胞损失，使用泛半胱天冬酶抑制剂ZVAD（N-苄氧羰基-Val-Ala-Asp-氟甲基酮）来拯救TH-ir细胞免受雌二醇介导的数量减少的影响。总之，这些数据表明，一个内在的细胞死亡途径激活雌激素调节TH-免疫反应细胞的数量。因此，与性类固醇在哺乳动物神经系统中更广泛的神经保护作用相反，在AVPV中，雌激素通过凋亡细胞死亡的半胱天冬酶依赖性机制调节多巴胺能神经元数量。
The sexually dimorphic population of dopamine neurons in the anteroventral periventricular nucleus of the preoptic region of the hypothalamus (AVPV) develops postnatally under the influence of testosterone, which is aromatized to estrogen. There are fewer dopaminergic neurons labeled with tyrosine hydroxylase (TH) in the male AVPV than the female, and sex steroids determine this sex difference, yet the role of cell death in specifying numbers of dopaminergic neurons in the AVPV is unknown. Estradiol treatment of the AVPV, in vivo and in vitro, was used to manipulate TH-ir cell number. In vitro, concurrent treatment with the estrogen receptor antagonist ICI 182,780 rescued TH-ir cells. Cyclosporin A, an inhibitor of cell death dependent on the opening of a mitochondrial permeability transition pore also blocked TH-ir cell loss. In vivo, estradiol increased the number of apoptotic profiles, both TUNEL and Hoechst labeled nuclei, in the AVPV. This increased apoptosis was also dependent on the presence of the α form of the estrogen receptor. To test for caspase dependent TH-ir cell loss, the pancaspase inhibitor ZVAD (N-benzyloxycabonyl-Val-Ala-Asp-fluoromethylketone) was used to rescue TH-ir cells from estradiol-mediated reduction in number. Together, these data suggest that an intrinsic cell death pathway is activated by estrogen to regulate TH-ir cell number. Thus, in contrast to the more widespread neuroprotective actions of sex steroids in the mammalian nervous system, in the AVPV estrogen regulates dopaminergic neuron number through a caspase-dependent mechanism of apoptotic cell death.