Cell-type-specific spatiotemporal expression of creatine biosynthetic enzyme S-adenosylmethionine: guanidinoacetate N-methyltransferase in developing mouse brain
Cell-type-specific spatiotemporal expression of creatine biosynthetic enzyme S-adenosylmethionine: guanidinoacetate N-methyltransferase in developing mouse brain
复制标题
发育中小鼠脑中肌酸生物合成酶 S-腺苷甲硫氨酸：胍基乙酸 N-甲基转移酶的细胞类型特异性时空表达
DOI：
10.1007/s11064-017-2446-y
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发表时间：
2018
期刊：
影响因子：
4.4
通讯作者：
Hosoya K.
中科院分区：
文献类型：
--
作者：
Tachikawa M;Watanabe M;Fukaya M;Sakai K;Terasaki T;Hosoya K.
肌酸是由肌酸转运蛋白(S-adenosylmethionine:guanidinoacetateN-methyltransferase，GAMT)合成的，肌酸激酶(CK)介导的肌酸/磷酸肌酸穿梭系统是细胞内高能磷酸盐储存和再生所必需的。尽管肌酸缺乏综合征的遗传性证明了该系统在脑发育中的重要性，但GAMT在发育脑中的时空细胞表达模式仍不清楚。在这里，我们展示了在发育中的小鼠大脑中发生了两波高GAMT表达。第一个涉及胚胎和新生儿阶段脑室区域和小脑外部颗粒层的有丝分裂细胞的高表达。第二种是在出生后第二周和第三周(即活跃的髓鞘形成阶段)启动对少突胶质细胞GAMT的调节，并持续到成年期。在其他类型的细胞中，明显的时间模式也很明显。GAMT在出生后高表达于血管周细胞和平滑肌细胞，但在成人中不表达。在神经元中，GAMT在位于脑室区的神经母细胞中低至中等水平，在出生后第二周树突和突触发生活跃时增加，此后下降到非常低的水平。在整个发育过程中，星形胶质细胞中观察到中等水平的表达。GAMT的高度调控、细胞类型依赖的表达表明局部肌酸的生物合成在神经发育的某些阶段发挥着关键作用。根据这一观点，我们观察到分化神经元中CK表达增加；这将增加肌酸/磷酸肌酸穿梭系统的活性，这可能反映了能量需求的增加。
Creatine is synthesized by S-adenosylmethionine:guanidinoacetateN-methyltransferase (GAMT), and the creatine/phosphocreatine shuttle system mediated by creatine kinase (CK) is essential for storage and regeneration of high-energy phosphates in cells. Although the importance of this system in brain development is evidenced by the hereditary nature of creatine deficiency syndrome, the spatiotemporal cellular expression patterns of GAMT in developing brain remain unknown. Here we show that two waves of high GAMT expression occur in developing mouse brain. The first involves high expression in mitotic cells in the ventricular zone of the brain wall and the external granular layer of the cerebellum at the embryonic and neonatal stages. The second was initiated by striking up-regulation of GAMT in oligodendrocytes during the second and third postnatal weeks (i.e., the active myelination stage), which continued to adulthood. Distinct temporal patterns were also evident in other cell types. GAMT was highly expressed in perivascular pericytes and smooth muscle cells after birth, but not in adults. In neurons, GAMT levels were low to moderate in neuroblasts residing in the ventricular zone, increased during the second postnatal week when active dendritogenesis and synaptogenesis occur, and decreased to very low levels thereafter. Moderate levels were observed in astrocytes throughout development. The highly regulated, cell type-dependent expression of GAMT suggests that local creatine biosynthesis plays critical roles in certain phases of neural development. In accordance with this idea, we observed increased CK expression in differentiating neurons; this would increase creatine/phosphocreatine shuttle system activity, which might reflect increased energy demand.