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bioRxiv · 10.1101/2024.06.28.601266

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

Diaz-Salazar, C.·KRZISCH, M. A.·Yoo, J.·Nano, P.·Bhaduri, A.·Jaenisch, R.·Polleux, F.
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Abstract

Microglia play key roles in shaping synaptic connectivity during neural circuits development. Whether microglia display human-specific features of structural and functional maturation is currently unknown. We show that the ancestral gene SRGAP2A and its human-specific (HS) paralogs SRGAP2B/C are not only expressed in cortical neurons but are the only HS gene duplications expressed in human microglia. Here, using combination of xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that (1) HS SRGAP2B/C are necessary and sufficient to induce neotenic features of microglia structural and functional maturation in a cell-autonomous manner, and (2) induction of SRGAP2-dependent neotenic features of microglia maturation non-cell autonomously impacts synaptic development in cortical pyramidal neurons. Our results reveal that, during human brain evolution, human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers of both neurons and microglia.

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Diaz-Salazar, C., KRZISCH, M. A., Yoo, J., Nano, P., Bhaduri, A., Jaenisch, R., Polleux, F.. 2024-06-29. Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation. https://doi.org/10.1101/2024.06.28.601266

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