Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Area of Science:

• Neuroscience
• Immunology
• Developmental Biology

Background:

• Early immune system disturbances are linked to increased risk of brain disorders.
• The precise mechanisms governing the functional maturation of microglia, the brain's resident immune cells, are not well understood.

Purpose of the Study:

• To reconstruct the developmental trajectory of microglia during the postnatal period.
• To identify key developmental switches and their impact on microglial function and brain health.

Main Methods:

• Utilized mathematical modeling of hippocampal and cerebellar development in mice.
• Investigated microglial development in repopulation contexts and the fetal human brain.
• Employed pharmacological and genetic perturbations, alongside analysis of cell-cycle dynamics, metabolic state, and chromatin remodeling.

Main Results:

• Identified a critical proliferative-to-quiescent (P/Q) switch in microglia around postnatal day 3/4.
• This P/Q switch precedes the acquisition of complex morphology and efficient phagocytosis.
• Disrupting proliferation impaired subsequent microglial maturation and phagocytic capacity, driven by the epigenetic regulator Ikaros.

Conclusions:

• Established key developmental milestones for microglia, including a crucial P/Q switch.
• Revealed an unexpected link between microglial proliferation and phagocytosis, critical for neurodevelopment.
• Highlights a potential period of early vulnerability in microglial development relevant to neurodegenerative disorders.