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이원영Wonyoung Lee

한국뇌연구원

EMBO J., 12 December 2024 | https://doi.org/10.1038/s44318-024-00325-9 Cyclin-dependent kinase inhibitor p18 regulates lineage transitions of excitatory neurons, astrocytes, and interneurons in the mouse cortex

Wonyoung Lee ¹, Byunghee Kang ², Hyo-Min Kim ³, Tsuyoshi Ishida ⁴, Minkyung Shin ¹, Misato Iwashita ¹, Masahiro Nitta ⁵, Aki Shiraishi ⁶, Hiroshi Kiyonari ⁶, Koichiro Shimoya ⁷, Kazuto Masamoto⁵, Tae-Young Roh ^8,* & Yoichi Kosodo^1,9,*

¹Neural Regeneration Lab, Neural Circuit Research Group, Korea Brain Research Institute, Daegu, Republic of Korea.
²Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
³College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
⁴Department of Obstetrics and Gynecology, Kobe Tokushukai Hospital, Kobe, Japan.
⁵Center for Neuroscience and Biomedical Engineering, The University of Electro-Communications, Tokyo, Japan.
⁶Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
⁷Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki, Japan.
⁸Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea.
⁹Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea.

^*Corresponding authors: correspondence to Tae-Young Roh or Yoichi Kosodo

Abstract

Neural stem cells (NSCs) can give rise to both neurons and glia, but the regulatory mechanisms governing their differentiation transitions remain incompletely understood. Here, we address the role of cyclin-dependent kinase inhibitors (CDKIs) in the later stages of dorsal cortical development. We find that the CDKIs p18 and p27 are upregulated at the onset of astrocyte generation. Acute manipulation of p18 and p27 levels shows that CDKIs modulate lineage switching between upper-layer neurons and astrocytes at the transitional stage. We generate a conditional knock-in mouse model to induce p18 in NSCs. The transcriptomic deconvolution of microdissected tissue reveals that increased levels of p18 promote glial cell development and activate Delta-Notch signaling. Furthermore, we show that p18 upregulates the homeobox transcription factor Dlx2 to subsequently induce the differentiation of olfactory bulb interneurons while reducing the numbers of upper-layer neurons and astrocytes at the perinatal stage. Clonal analysis using transposon-based reporters reveals that the transition from the astrocyte to the interneuron lineage is potentiated by p18 at the single-cell level. In sum, our study reports a function of p18 in determining the developmental boundaries among different cellular lineages arising sequentially from NSCs in the dorsal cortex.

논문정보

형식Research article
게재일2024년 12월 (BRIC 등록일 2024-12-13)
연구진국내(교신)+국외 연구진
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