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Dihydrofolate reductase activity controls neurogenic transitions in the developing neocortex
Sulov Saha1, Thomas T Jungas1, David Ohayon1
1Molecular, Cellular and Developmental Biology Unit (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 118 route de Narbonne, 31062 Toulouse, France.
Development (Cambridge, England)
|September 4, 2023
Summary
Reducing dihydrofolate reductase (DHFR) activity in developing neocortex accelerates neurogenesis and alters neuronal composition. This highlights the critical role of one-carbon metabolism in neural development and cell fate.
Area of Science:
- Developmental Neuroscience
- Metabolic Biochemistry
- Epigenetics
Background:
- One-carbon/folate (1C) metabolism is crucial for methylation processes essential for stem cell self-renewal.
- Dihydrofolate reductase (DHFR) is a key enzyme in 1C metabolism, highly expressed during early neocortical development.
Purpose of the Study:
- To investigate the role of DHFR in neocortical development.
- To understand how DHFR activity influences neurogenesis and neuronal composition.
Main Methods:
- Utilized human neural organoids and mouse embryonic neocortex models.
- Reduced DHFR activity and analyzed effects on neurogenesis and metabolite levels.
- Assessed epigenetic modifications, specifically H3K4me3 levels.
Main Results:
- Decreased DHFR activity accelerated indirect neurogenesis in both human and mouse models.
- Reduced 1C metabolites and altered H3K4me3 levels were observed with diminished DHFR activity.
- Neuronal composition of the neocortex was affected by changes in DHFR activity.
Conclusions:
- DHFR plays an unexpected role in regulating neocortex development.
- Variations in 1C metabolic cues significantly impact neural progenitor cell fate transitions.
- DHFR activity is a key determinant in controlling neurogenesis and neuronal differentiation.
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