Dehydroepiandrosterone: A potential signalling molecule for neocortical organization during development
Dehydroepiandrosterone: A potential signalling molecule for neocortical organization during development
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DOI：
10.1073/pnas.95.8.4678
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发表时间：
1998-04-14
影响因子：
11.1
通讯作者：
Mellon, SH
中科院分区：
文献类型：
--
作者：
Compagnone, NA;Mellon, SH
脱氢表雄酮（DHEA）及其硫酸盐衍生物（DHEAS）是由人类肾上腺产生的最丰富的类固醇，但除了作为性类固醇合成的前体外，还没有鉴定出这些类固醇的受体，也没有确定它们的功能。DHEA和DHEAS存在于许多物种的大脑中，我们已经证明，对它们的合成至关重要的酶，特别是P450 c17（17 α-羟化酶/c17，20裂解酶），在发育中的啮齿动物大脑中以发育调节的区域特异性方式表达。P450 c17胚胎表达的一个区域，即新皮质亚板，被认为在引导皮质投射到适当目标方面发挥作用。因此，我们确定，如果产品的P450 c17活性，DHEA和DHEAS，调节运动和/或生长的新皮层神经元，在原代培养的小鼠胚胎新皮层神经元，DHEA增加的长度轴突标记Tau-1，静脉曲张和篮状突起的形成，以剂量依赖性的方式。这些影响可以在大脑中正常发现的浓度下观察到。相比之下，DHEAS对Tau-1轴突神经突没有影响，但增加了含有树突标记物微管相关蛋白-2的神经突的长度。DHEA通过激活N-甲基-D-天冬氨酸（NMDA）受体，迅速增加细胞内游离钙。这些研究为DHEA和DHEAS发挥生物学作用的机制提供了证据，表明它们除了作为性类固醇前体外，还黑尔特殊的功能，通过非经典的类固醇激素受体介导其作用，并表明它们在体内的发育调节合成可能在组织新皮层中发挥关键和不同的作用。
Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEAS) are the most abundant steroids produced by the human adrenal, but no receptors have been identified for these steroids, and no function for them has been established, other than as precursors for sex steroid synthesis. DHEA and DHEAS are found in brains from many species, and we have shown that enzymes crucial for their synthesis, especially P450c17 (17 alpha-hydroxylase/c17,20 lyase), are expressed in a developmentally regulated, region-specific fashion in the developing rodent brain. One region of embryonic expression of P450c17, the neocortical subplate, has been postulated to play a role in guiding cortical projections to their appropriate targets. We therefore determined if products of P450c17 activity, DHEA and DHEAS, regulated the motility and/or growth of neocortical neurons, In primary cultures of mouse embryonic neocortical neurons, DHEA increased the length of neurites containing the axonal marker Tau-1, and the incidence of varicosities and basket-like process formations in a dose-dependent fashion. These effects could be seen at concentrations normally found in the brain. By contrast, DHEAS had no effect on Tau-1 axonal neurites but increased the length of neurites containing the dendritic marker microtubule-associated protein-2. DHEA rapidly increased free intracellular calcium,ia activation of N-methyl-D-aspartate (NMDA) receptors, These studies provide evidence of mechanisms by which DHEA and DHEAS exert biological actions, show that they hale specific functions other than as sex steroid precursors, mediate their effects ria nonclassic steroid hormone receptors, and suggest that their developmentally regulated synthesis in vivo may play crucial and different roles in organizing the neocortex.