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Updated: May 4, 2026
Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells NPCs
Published on: March 2, 2018
Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells
Nobuhiro Kurabayashi1, Kamon Sanada
1Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract:
Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS.
Insights
Down's syndrome (DS) neurodevelopmental defects stem from chromosome 21 gene dosage. DYRK1A and DSCR1 genes
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Down's syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21, leading to intellectual disability.
- Neural progenitor cells in the developing neocortex are crucial for brain formation.
Purpose of the Study:
- To investigate the role of DYRK1A and DSCR1 genes in neurodevelopmental defects associated with Down's syndrome.
- To elucidate the mechanism by which these genes affect neuronal differentiation and fate.
Main Methods:
- Studied gene expression and protein dosage in mouse neural progenitors.
- Utilized the Ts1Cje mouse model for Down's syndrome research.
- Analyzed the activity of the transcription factor NFATc.
Main Results:
- Increased dosage of DYRK1A and DSCR1 delayed neuronal differentiation and altered cell fate in mouse neocortex.
- DYRK1A and DSCR1 cooperatively suppressed NFATc activity, impacting neurogenesis.
- Ts1Cje mice exhibited dysregulated NFATc, elevated DYRK1A/DSCR1 levels, and impaired neurogenesis.
Conclusions:
- Gene dosage of DYRK1A and DSCR1 is critical for normal neurogenesis via NFATc regulation.
- This pathway provides a potential explanation for neurodevelopmental deficits observed in Down's syndrome.
- Targeting this pathway may offer therapeutic strategies for DS-related neurodevelopmental issues.
