Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• The human brain exhibits prolonged developmental timing (neoteny).
• Genetic mechanisms controlling neoteny across brain cell types are not fully understood.
• Microglia, the brain's immune cells, play crucial roles in development and function.

Purpose of the Study:

• To investigate the genetic mechanisms behind neotenic maturation in human cortical microglia.
• To identify human-specific genes involved in microglial development.
• To understand the role of these genes in synaptic development and circuit formation.

Main Methods:

• Comparative analysis of human and mouse cortical microglia.
• Identification of human-specific gene duplications in microglia.
• Xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia.
• Utilizing mouse genetic models to study gene function.

Main Results:

• Human cortical microglia show neotenic structural and transcriptional maturation compared to mouse microglia.
• SRGAP2B/C, human-specific gene paralogs, are expressed in human microglia.
• SRGAP2B/C are necessary and sufficient to induce neotenic microglial maturation.
• Neotenic microglial maturation alters the timing of synaptic development.

Conclusions:

• Human-specific SRGAP2B/C genes are key regulators of neotenic microglial maturation.
• Microglial developmental timing is linked to the timing of neural circuit formation.
• SRGAP2B/C likely coordinated neotenic synaptic development in human brain evolution by acting in both neurons and microglia.