Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development

Lei Shi; Xin Luo; Jin Jiang; Yongchang Chen; Cirong Liu; Ting Hu; Min Li; Qiang Lin; Yanjiao Li; Jun Huang; Hong Wang; Yuyu Niu; Yundi Shi; Martin Styner; Jianhong Wang; Yi Lu; Xuejin Sun; Hualin Yu; Weizhi Ji; Bing Su

doi:10.1093/nsr/nwz043

Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development

Natl Sci Rev. 2019 May;6(3):480-493. doi: 10.1093/nsr/nwz043. Epub 2019 Mar 27.

Authors

Lei Shi^{1

2

3}, Xin Luo^{1

2

3

4}, Jin Jiang^{1

2

3

4}, Yongchang Chen⁵, Cirong Liu¹, Ting Hu^{1

2

3

4}, Min Li¹, Qiang Lin¹, Yanjiao Li¹, Jun Huang¹, Hong Wang⁵, Yuyu Niu⁵, Yundi Shi⁶, Martin Styner^{6

7}, Jianhong Wang⁸, Yi Lu⁹, Xuejin Sun⁹, Hualin Yu¹⁰, Weizhi Ji⁵, Bing Su^{1

2

3}

Affiliations

¹ State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
² Primate Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
³ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
⁴ Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100101, China.
⁵ Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translation Medicine, Kunming University of Science and Technology, Kunming 650500, China.
⁶ Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599-7160, USA.
⁷ Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599-7160, USA.
⁸ Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
⁹ Department of Medical Imaging, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
¹⁰ Department of Minimally Invasive Neurosurgery, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.

Abstract

Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1, an important gene for brain development and brain evolution. Brain-image and tissue-section analyses indicated an altered pattern of neural-cell differentiation, resulting in a delayed neuronal maturation and neural-fiber myelination of the transgenic monkeys, similar to the known evolutionary change of developmental delay (neoteny) in humans. Further brain-transcriptome and tissue-section analyses of major developmental stages showed a marked human-like expression delay of neuron differentiation and synaptic-signaling genes, providing a molecular explanation for the observed brain-developmental delay of the transgenic monkeys. More importantly, the transgenic monkeys exhibited better short-term memory and shorter reaction time compared with the wild-type controls in the delayed-matching-to-sample task. The presented data represent the first attempt to experimentally interrogate the genetic basis of human brain origin using a transgenic monkey model and it values the use of non-human primates in understanding unique human traits.

Keywords: MCPH1; brain development; cognition; human evolution; neoteny; transgenic monkey.