International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
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Abnormal Development of Neural Stem Cell Niche in the Dentate Gyrus of Menkes Disease

  • Sung-kuk Cho (Cell Therapy Research Center, GC Cell) ;
  • Suhyun Gwon (Cell Therapy Research Center, GC Cell) ;
  • Hyun Ah Kim (Cell Therapy Research Center, GC Cell) ;
  • Jiwon Kim (Department of Neurology, Dongguk University Ilsan Hospital) ;
  • Sung Yoo Cho (Cell Therapy Research Center, GC Cell) ;
  • Dong-Eog Kim (Department of Neurology, Dongguk University Ilsan Hospital) ;
  • Jong-Hee Chae (Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine) ;
  • Dae Hwi Park (Cell Therapy Research Center, GC Cell) ;
  • Yu Kyeong Hwang (Cell Therapy Research Center, GC Cell)
  • Received : 2021.05.05
  • Accepted : 2021.12.19
  • Published : 2022.08.30
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Abstract

Background and Objectives: Menkes disease (MNK) is a rare X-linked recessive disease, caused by mutations in the copper transporting ATP7A gene that is required for copper homeostasis. MNK patients experience various clinical symptoms including neurological defects that are closely related to the prognosis of MNK patients. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) produce new neurons throughout life, and defects in DG neurogenesis are often correlated with cognitive and behavioral problems. However, neurodevelopmental defects in the DG during postnatal period in MNK have not been understood yet. Methods and Results: Mottled-brindled (MoBr/y) mice (MNK mice) and littermate controls were used in this study. In vivo microCT imaging and immunohistochemistry results demonstrate that blood vasculatures in hippocampus are abnormally decreased in MNK mice. Furthermore, postnatal establishment of NSC population and their neurogenesis are severely compromised in the DG of MNK mice. In addition, in vitro analyses using hippocampal neurosphere culture followed by immunocytochemistry and immunoblotting suggest that neurogenesis from MNK NSCs is also significantly compromised, corresponding to defective neurogenic gene expression in MNK derived neurons. Conclusions: Our study is the first reports demonstrating that improper expansion of the postnatal NSC population followed by significant reduction of neurogenesis may contribute to neurodevelopmental symptoms in MNK. In conclusion, our results provide new insight into early neurodevelopmental defects in MNK and emphasize the needs for early diagnosis and new therapeutic strategies in the postnatal central nerve system damage of MNK patients.

Keywords

Acknowledgement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI12C0066).

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