A concerted metabolic shift in early forebrain alters the CSF proteome and depends on MYC downregulation for mitochondrial maturation
A concerted metabolic shift in early forebrain alters the CSF proteome and depends on MYC downregulation for mitochondrial maturation
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DOI：
10.1242/dev.182857
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发表时间：
2019-10-01
期刊：
影响因子：
4.6
通讯作者：
Lehtinen, Maria K.
中科院分区：
文献类型：
--
作者：
Fame, Ryann M.;Shannon, Morgan L.;Lehtinen, Maria K.
中枢神经系统（CNS）祖细胞从前脑神经外胚层细胞向特定神经上皮细胞的转变伴随着大规模、协调的细胞变化。我们之前发现，MYC 在胚胎 E8.5 和 E10.5 天（神经管闭合之前和之后；NTC）调节小鼠前脑前体中核糖体和蛋白静态景观的变化（Chau 等人，2018）。在这里，我们展示了在前脑规范的同一阶段代谢机制中平行协调的转录变化。祖细胞表现出显着的线粒体结构变化，从 E8.5 的糖酵解嵴过渡到 E10.5 的更传统的线粒体。因此，祖细胞中葡萄糖的使用发生了变化，使得 E8.5 祖细胞依赖于糖酵解，并且在 NTC 之后越来越多地使用氧化磷酸化。这种代谢变化与周围羊水和脑脊液蛋白质组的变化相匹配。重要的是，这些线粒体形态变化取决于 MYC 下调。总之，我们的研究结果表明，在前脑发育的最早阶段，代谢转变伴随着祖细胞的动态细胞器和蛋白质抑制重塑。
Massive, coordinated cellular changes accompany the transition of central nervous system (CNS) progenitors from forebrain neurectodermal cells to specified neuroepithelial cells. We have previously found that MYC regulates the changing ribosomal and proteostatic landscapes in mouse forebrain precursors at embryonic days E8.5 and E10.5 (before and after neural tube closure; NTC) (Chau et al., 2018). Here, we demonstrate parallel coordinated transcriptional changes in metabolic machinery during this same stage of forebrain specification. Progenitors showed striking mitochondrial structural changes transitioning from glycolytic cristae at E8.5, to more traditional mitochondria at E10.5. Accordingly, glucose use shifted in progenitors such that E8.5 progenitors relied on glycolysis, and after NTC increasingly used oxidative phosphorylation. This metabolic shift was matched by changes in surrounding amniotic and cerebrospinal fluid proteomes. Importantly, these mitochondrial morphological shifts depend on MYC downregulation. Together, our findings demonstrate that metabolic shifting accompanies dynamic organelle and proteostatic remodeling of progenitor cells during the earliest stages of forebrain development.