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Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation

Carlos Diaz-Salazar1,2, Marine Krzisch3, Juyoun Yoo1,2

  • 1Department of Neuroscience, Columbia University, New York, NY, 10027, USA.

Biorxiv : the Preprint Server for Biology
|July 9, 2024
PubMed

Insights

Human-specific genes SRGAP2B/C drive neotenic maturation in human microglia, influencing synaptic development. This reveals how these genes shaped brain evolution by modifying both neurons and microglia.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Microglia are crucial for synaptic development in neural circuits.
  • The human-specific maturation of microglia remains largely unexplored.
  • The role of human-specific gene duplications, like SRGAP2B/C, in microglia is unknown.

Purpose of the Study:

  • To investigate whether human-specific genes influence microglia maturation.
  • To determine the role of SRGAP2B/C in microglia structural and functional development.
  • To understand the impact of SRGAP2-mediated microglia maturation on synaptic development.

Main Methods:

  • Xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia into mouse models.
  • Utilizing mouse genetic models to study SRGAP2 gene functions.
  • Analyzing structural and functional maturation of microglia and synaptic development in cortical neurons.

Main Results:

  • Human-specific SRGAP2B/C genes are uniquely expressed in human microglia.
  • SRGAP2B/C are necessary and sufficient for cell-autonomous neotenic maturation of microglia.
  • SRGAP2-dependent microglia maturation non-cell autonomously affects synaptic development in cortical pyramidal neurons.

Conclusions:

  • Human-specific genes SRGAP2B/C are key drivers of neotenic microglia maturation.
  • SRGAP2B/C act as genetic modifiers in both neurons and microglia.
  • These genes coordinated the evolution of neotenic synaptic development in the human brain.

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