2. Academic Validation
  3. Spatiotemporal Expression of IRS-1 During Brain Development and its Role in Neural Stem Cell Differentiation

Spatiotemporal Expression of IRS-1 During Brain Development and its Role in Neural Stem Cell Differentiation

  • Neuromolecular Med. 2025 May 2;27(1):32. doi: 10.1007/s12017-025-08853-1.
Junjiao Zhang 1 2 3,  Xiao Li # 1 2 3,  Fan Zhang 1 2 3,  Hongyuan Chu 1 2 3,  Jingmin Wang 1 2 3 4,  Ye Wu 1 2 3 5,  Kai Gao 6 7 8 9,  Yuwu Jiang 10 11 12 13 14
Affiliations

Affiliations

  • 1 Children's Medical Center, Peking University First Hospital, No. 5 Leyuan Road, Daxing District, Beijing, 102627, China.
  • 2 Beijing Key Laboratory of Molecular Diagnosis and Study On Pediatric Genetic Diseases, Beijing, China.
  • 3 Children Epilepsy Center, Peking University First Hospital, Beijing, China.
  • 4 Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China.
  • 5 Children's Medical Center, Peking University First Hospital, No. 1 Xi'an Men Street, West District, Beijing, 100034, China.
  • 6 Children's Medical Center, Peking University First Hospital, No. 5 Leyuan Road, Daxing District, Beijing, 102627, China. gaokaipku@bjmu.edu.cn.
  • 7 Beijing Key Laboratory of Molecular Diagnosis and Study On Pediatric Genetic Diseases, Beijing, China. gaokaipku@bjmu.edu.cn.
  • 8 Children Epilepsy Center, Peking University First Hospital, Beijing, China. gaokaipku@bjmu.edu.cn.
  • 9 Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China. gaokaipku@bjmu.edu.cn.
  • 10 Children's Medical Center, Peking University First Hospital, No. 5 Leyuan Road, Daxing District, Beijing, 102627, China. jiangyuwu@bjmu.edu.cn.
  • 11 Beijing Key Laboratory of Molecular Diagnosis and Study On Pediatric Genetic Diseases, Beijing, China. jiangyuwu@bjmu.edu.cn.
  • 12 Children Epilepsy Center, Peking University First Hospital, Beijing, China. jiangyuwu@bjmu.edu.cn.
  • 13 Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China. jiangyuwu@bjmu.edu.cn.
  • 14 Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China. jiangyuwu@bjmu.edu.cn.
  • # Contributed equally.
PMID: 40314831 DOI: 10.1007/s12017-025-08853-1
Abstract

Insulin Receptor substrate 1 (IRS-1) is a key mediator of Insulin signaling linked to focal cortical dysplasia. While previous studies have primarily focused on IRS-1 in peripheral tissues, its function in the central nervous system has remained largely unexplored. This study aimed to investigate the spatiotemporal expression patterns of IRS-1 protein in mouse cerebral cortex and human brain organoids, along with its role in neural development. In mice, Irs-1 expression was consistent throughout brain development, with notable localization in the ventricular/subventricular zone during early gestation and later in the outer cerebral cortex. In human brain organoids, IRS-1 was primarily found in rosette structures initially, shifting to the outer cortical layer as they matured. Knockdown of Irs-1 at embryonic day 14.5 via in-utero electroporation impaired neuronal migration, resulting in more neurons remaining in the intermediate zone compared to controls. Moreover, SH-SY5Y cells treated with isotretinoin exhibited a significant decrease in IRS-1 protein expression during maturation. RNA Sequencing indicates an upregulation of neurodevelopment-related genes alongside a downregulation of the IRS-1. These findings underscore the significance of IRS-1 in brain development, particularly regarding neuronal migration and differentiation.

Keywords

Brain organoid; IRS-1; Isotretinoin; Neuronal differentiation; SH-SY5Y.

Figures
Products