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Updated: Oct 2, 2025
Assaying Circuit Specific Regulation of Adult Hippocampal Neural Precursor Cells
Published on: July 24, 2019
Abnormal Development of Neural Stem Cell Niche in the Dentate Gyrus of Menkes Disease
Sung-Kuk Cho1, Suhyun Gwon1, Hyun Ah Kim1
1Cell Therapy Research Center, GC Cell, Yongin, Korea.
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.
Insights
Menkes disease (MNK) impairs neural stem cell (NSC) neurogenesis in the hippocampus, leading to developmental defects. This study reveals compromised NSC expansion and reduced neurogenesis in MNK mice, highlighting the need for early intervention.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Menkes disease (MNK) is a rare X-linked recessive disorder caused by ATP7A gene mutations, affecting copper homeostasis and causing neurological defects.
- Defects in hippocampal neurogenesis are linked to cognitive and behavioral issues, but postnatal neurodevelopmental impacts in MNK remain unclear.
Purpose of the Study:
- To investigate neurodevelopmental defects in the hippocampal dentate gyrus (DG) during the postnatal period in Menkes disease.
- To elucidate the role of neural stem cells (NSCs) and neurogenesis in the DG of MNK.
Main Methods:
- Utilized Mottled-brindled (MoBr/y) mice as an MNK model.
- Employed in vivo microCT imaging, immunohistochemistry, and in vitro neurosphere culture with immunocytochemistry and immunoblotting.
Main Results:
- MNK mice exhibited decreased hippocampal vasculature and severely compromised postnatal NSC population establishment and neurogenesis in the DG.
- In vitro studies confirmed significantly reduced neurogenesis from MNK NSCs, associated with defective neurogenic gene expression.
Conclusions:
- This study is the first to demonstrate that improper expansion of postnatal NSC populations and reduced neurogenesis contribute to neurodevelopmental symptoms in MNK.
- Findings offer new insights into early neurodevelopmental defects in MNK, stressing the importance of early diagnosis and therapeutic strategies for postnatal central nervous system damage.
