Akaba Yuichi, Takahashi Satoru, Suzuki Keiichiro, Kosaki Kenjiro, Tsujimura Keita
Group of Brain Function and Development, Neuroscience Institute of the Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan.
Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya, Aichi, Japan.
Front Cell Dev Biol. 2023 Feb 7;11:1096463. doi: 10.3389/fcell.2023.1096463. eCollection 2023.
Proper development and function of the central nervous system require precise regulation of gene expression. MicroRNAs (miRNAs), a group of small non-coding RNAs that can negatively regulate gene expression at the post-transcriptional level, are critical regulators of neuronal development, and dysregulation of microRNAs has been implicated in various neurological disorders. Changes in microRNA expression and repertoire are related to the emergence of social and behavioral variations in closely related primates, including humans, during evolution. MicroRNA-514a (miR-514a) is an X-linked miRNA that is conserved in species with higher social and cognitive functions, and frequent tandem duplications of miR-514a have been found in primate genomes. Here, we demonstrate that miR-514a plays a crucial role in neuronal development in neurons derived from human induced pluripotent stem cells (iPSCs). Overexpression of miR-514a increased dendritic length, soma size, and activity levels of mammalian target of rapamycin (mTOR) signaling in induced pluripotent stem cell-derived neurons, whereas blocking of endogenous miR-514a inhibited neuronal development. Furthermore, we performed a functional analysis of the miR-514a variation found during primate evolution, to investigate the impact of miR-514a sequence variation and associated changes in expression on brain development during evolution. We found that mutation in miR-514a significantly reduced the expression of the mature form and abolished the effects observed when native miR-514a was expressed. Our findings provide new insights into the functional role of miR-514a in the regulation of neuronal development and evolution of primate brain development.
中枢神经系统的正常发育和功能需要基因表达的精确调控。微小RNA（miRNA）是一类小的非编码RNA，可在转录后水平负调控基因表达，是神经元发育的关键调节因子，微小RNA的失调与包括人类在内的密切相关灵长类动物在进化过程中出现的各种神经紊乱有关。微小RNA表达和种类的变化与密切相关的灵长类动物（包括人类）在进化过程中社会和行为变异的出现有关。微小RNA-514a（miR-514a）是一种X连锁的微小RNA，在具有较高社会和认知功能的物种中保守，并且在灵长类动物基因组中发现了miR-514a的频繁串联重复。在这里，我们证明miR-514a在源自人类诱导多能干细胞（iPSC）的神经元的神经元发育中起关键作用。miR-514a的过表达增加了诱导多能干细胞衍生神经元中雷帕霉素哺乳动物靶标（mTOR）信号传导的树突长度、胞体大小和活性水平，而内源性miR-514a的阻断则抑制了神经元发育。此外，我们对灵长类动物进化过程中发现的miR-514a变异进行了功能分析，以研究miR-514a序列变异和相关表达变化对进化过程中大脑发育的影响。我们发现miR-514a中的突变显著降低了成熟形式的表达，并消除了表达天然miR-514a时观察到的效果。我们的研究结果为miR-514a在调节神经元发育和灵长类动物大脑发育进化中的功能作用提供了新的见解。
