Brain developmental and cortical connectivity changes in transgenic monkeys carrying the human-specific duplicated gene SRGAP2C

Xiaoyu Meng; Qiang Lin; Xuerui Zeng; Jin Jiang; Min Li; Xin Luo; Kaimin Chen; Haixu Wu; Yan Hu; Cirong Liu; Bing Su

doi:10.1093/nsr/nwad281

Brain developmental and cortical connectivity changes in transgenic monkeys carrying the human-specific duplicated gene SRGAP2C

Natl Sci Rev. 2023 Nov 3;10(11):nwad281. doi: 10.1093/nsr/nwad281. eCollection 2023 Nov.

Authors

Xiaoyu Meng^{1

2

3}, Qiang Lin¹, Xuerui Zeng^{1

2

3}, Jin Jiang¹, Min Li¹, Xin Luo^{1

2}, Kaimin Chen^{1

2

3}, Haixu Wu^{1

2

3}, Yan Hu¹, Cirong Liu⁴, Bing Su^{1

2

5}

Affiliations

¹ State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
² National Resource Center for Non-Human Primates, Kunming Primate Research Center, and National Research Facility for Phenotypic and Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650107, China.
³ Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100101, China.
⁴ Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.

Abstract

Human-specific duplicated genes contributed to phenotypic innovations during the origin of our own species, such as an enlarged brain and highly developed cognitive abilities. While prior studies on transgenic mice carrying the human-specific SRGAP2C gene have shown enhanced brain connectivity, the relevance to humans remains unclear due to the significant evolutionary gap between humans and rodents. In this study, to investigate the phenotypic outcome and underlying genetic mechanism of SRGAP2C, we generated transgenic cynomolgus macaques (Macaca fascicularis) carrying the human-specific SRGAP2C gene. Longitudinal MRI imaging revealed delayed brain development with region-specific volume changes, accompanied by altered myelination levels in the temporal and occipital regions. On a cellular level, the transgenic monkeys exhibited increased deep-layer neurons during fetal neurogenesis and delayed synaptic maturation in adolescence. Moreover, transcriptome analysis detected neotenic expression in molecular pathways related to neuron ensheathment, synaptic connections, extracellular matrix and energy metabolism. Cognitively, the transgenic monkeys demonstrated improved motor planning and execution skills. Together, our findings provide new insights into the mechanisms by which the newly evolved gene shapes the unique development and circuitry of the human brain.

Keywords: SRGAP2C; brain development; brain evolution; neoteny; neurogenesis; transgenic monkey.