Dihydrofolate reductase activity controls neurogenic transitions in the developing neocortex

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.