Laboratory for Spinal Cord Development and Regeneration, Department of Neurological Surgery, University of California San Francisco, CA, USA.
Front Endocrinol (Lausanne). 2012 Feb 7;3:16. doi: 10.3389/fendo.2012.00016. eCollection 2012.
Dehydroepiandrosterone (DHEA) is synthesized from cholesterol by activity of P450scc and P450c17, enzymes that we previously characterized in the developing nervous system. We describe the localization of P450c17 in the differentiated field of the ventral spinal cord in different motor neuron subtypes. We show that, during organogenesis, P450c17 activity is regulated along the antero/posterior axis of the spinal cord concomitantly with the gradient of neurogenesis. To examine whether DHEA may modulate this process, we measured proliferation and differentiation of ventral neural precursors in primary and explant cultures. Our results showed that DHEA-induced the expression of class II protein Nkx6.1, motor neuron precursor Olig-2, and definitive motor neuron marker Isl-1/2. DHEA also promoted proliferation of ventrally committed precursors in isolated spinal cord precursor cultures and in whole spinal cord explants. Both the proliferative and inductive effects of DHEA were dependent on sonic hedgehog signaling. The possibilities that the effects observed with DHEA were due to its metabolism into androgens or to activation of NMDA receptors were excluded. These results support the hypothesis that the tight regulation of DHEA biosynthesis may be a biologic clock restricting the period of ventral neuronal-precursor proliferation, thus controlling the number of pre-committed neurons in the developing neural tube.
脱氢表雄酮（DHEA）是由 P450scc 和 P450c17 这两种酶从胆固醇合成的，我们之前已经在发育中的神经系统中对这两种酶进行了特性描述。我们描述了 P450c17 在不同运动神经元亚型的腹侧脊髓分化区域的定位。我们表明，在器官发生期间，P450c17 活性沿着脊髓的前后轴与神经发生的梯度一起受到调节。为了研究 DHEA 是否可以调节这个过程，我们在原代和器官培养物中测量了腹侧神经前体细胞的增殖和分化。我们的结果表明，DHEA 诱导了 II 类蛋白 Nkx6.1、运动神经元前体细胞 Olig-2 和确定运动神经元标记物 Isl-1/2 的表达。DHEA 还促进了分离的脊髓前体细胞培养物和整个脊髓器官培养物中腹侧定向前体细胞的增殖。DHEA 的增殖和诱导作用都依赖于 sonic hedgehog 信号。排除了观察到的 DHEA 作用是由于其代谢为雄激素或激活 NMDA 受体的可能性。这些结果支持了这样一种假设，即 DHEA 生物合成的严格调节可能是一个生物钟，限制了腹侧神经元前体细胞增殖的时期，从而控制了发育中的神经管中预先承诺的神经元的数量。
