miR-514a promotes neuronal development in human iPSC-derived neurons

Yuichi Akaba; Satoru Takahashi; Keiichiro Suzuki; Kenjiro Kosaki; Keita Tsujimura

doi:10.3389/fcell.2023.1096463

miR-514a promotes neuronal development in human iPSC-derived neurons

Front Cell Dev Biol. 2023 Feb 7:11:1096463. doi: 10.3389/fcell.2023.1096463. eCollection 2023.

Authors

Yuichi Akaba^{1

2

3}, Satoru Takahashi³, Keiichiro Suzuki^{4

5

6}, Kenjiro Kosaki⁷, Keita Tsujimura^{1

2}

Affiliations

¹ Group of Brain Function and Development, Neuroscience Institute of the Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan.
² Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya, Aichi, Japan.
³ Department of Pediatrics, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
⁴ Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan.
⁵ Graduate School of Engineering Science, Osaka University, Osaka, Japan.
⁶ Graduate School of Frontier Bioscience, Osaka University, Osaka, Japan.
⁷ Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Abstract

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.

Keywords: IPSC; dendrite; mTOR; miR-514a; microRNA; neuronal development.

Grants and funding

This research was funded by the Japan Agency for Medical Research and Development (AMED) (JP22ek0109498 and JP22ek0109485) and the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP21K06834).