Gago Nathalie, El-Etr Martine, Sananès Nicole, Cadepond Françoise, Samuel Denise, Avellana-Adalid Virginia, Baron-Van Evercooren Anne, Schumacher Michael
INSERM U 488, Bicêtre, France.
J Neurosci Res. 2004 Dec 15;78(6):770-83. doi: 10.1002/jnr.20348.
The earliest identified neonatal neural progenitors are cells that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). One of these progenitors is the early PSA-NCAM+ progenitor (ePSA-NCAM+ progenitor; Gago et al. [2003] Mol Cell Neurosci 22:162-178), which corresponds to a multipotential cell with a default differentiation through glial lineages. The ePSA-NCAM+ progenitor can synthesize the neurosteroid progesterone (PROG) and its reduced metabolite 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP, or allopregnanolone; Gago et al. [ 2001] Glia 36:295-308). The latter is a potent positive allosteric modulator of gamma-aminobutyric acid type A (GABAA) receptors. In the present work, we demonstrate that PROG and 3alpha,5alpha-THP both stimulate ePSA-NCAM+ progenitor proliferation. PROG exerted its mitogenic effect indirectly, through its conversion to 3alpha,5alpha-THP, since it could be abolished by an inhibitor of the 5alpha-reductase (L685-273) and mimicked by 3alpha,5alpha-THP. A dose-response curve revealed a bell-shaped effect of 3alpha,5alpha-THP on ePSA-NCAM+ progenitor proliferation, with greatest stimulation at nanomolar concentrations. The mitogenic effect of 3 alpha,5 alpha-THP was mediated by GABAA receptors, insofar as it could be blocked by the selective antagonist bicuculline. ePSA-NCAM+ progenitors indeed expressed mRNAs for GABAA receptor subunits, and GABA enhanced cell proliferation, an effect that was also bicuculline sensitive. Moreover, these cells synthesized GABA, which was involved in a tonic stimulation of their proliferation. These results reveal complex autocrine/paracrine loops in the control of ePSA-NCAM+ progenitor proliferation, involving both neurosteroid and GABA signaling, and suggest a novel key role for 3alpha,5alpha-THP in the development of the nervous system.
最早被鉴定出的新生神经祖细胞是表达神经细胞黏附分子多唾液酸化形式（PSA-NCAM）的细胞。其中一种祖细胞是早期PSA-NCAM+祖细胞（ePSA-NCAM+祖细胞；加戈等人[2003年]《分子与细胞神经科学》22卷：162 - 178页），它相当于一种具有通过胶质细胞谱系进行默认分化能力的多能细胞。ePSA-NCAM+祖细胞能够合成神经甾体孕酮（PROG）及其还原代谢产物3α,5α-四氢孕酮（3α,5α-THP，即别孕烯醇酮；加戈等人[2001年]《神经胶质细胞》36卷：295 - 308页）。后者是γ-氨基丁酸A型（GABAA）受体的一种强效正性变构调节剂。在本研究中，我们证明PROG和3α,5α-THP均能刺激ePSA-NCAM+祖细胞增殖。PROG通过转化为3α,5α-THP间接发挥其促有丝分裂作用，因为其作用可被5α-还原酶抑制剂（L685 - 273）消除，且能被3α,5α-THP模拟。剂量反应曲线显示3α,5α-THP对ePSA-NCAM+祖细胞增殖具有钟形效应，在纳摩尔浓度时刺激作用最强。3α,5α-THP的促有丝分裂作用由GABAA受体介导，因为它可被选择性拮抗剂荷包牡丹碱阻断。ePSA-NCAM+祖细胞确实表达GABAA受体亚基的mRNA，且γ-氨基丁酸可增强细胞增殖，这一效应也对荷包牡丹碱敏感。此外，这些细胞合成γ-氨基丁酸，其参与对细胞增殖的持续性刺激。这些结果揭示了在ePSA-NCAM+祖细胞增殖控制中复杂的自分泌/旁分泌环路，涉及神经甾体和γ-氨基丁酸信号传导，并提示3α,5α-THP在神经系统发育中具有新的关键作用。
