Human-specific paralogs of SRGAP2 induce neotenic features of microglia maturation and impact synaptic development

One of the most salient features of human brain development is the considerably prolonged, neotenic, timing of synaptic development compared to other mammals including non-human primates. Microglia play key roles in shaping synaptic connectivity during neural circuits development. However, the structural and functional features of human microglia maturation remain poorly studied. Here, we first demonstrate that human and mouse cortical microglia follow similar developmental trajectories, albeit at strikingly different timescales in vivo. The ancestral gene SRGAP2A and its human-specific paralogs SRGAP2B/C are not only expressed in cortical neurons where they control the timing of synaptic maturation but also that SRGAP2B/C are the only human-specific gene duplications (HSGDs) expressed in human microglia. Using combinations of xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that (1) HS SRGAP2B/C, by inhibiting SRGAP2A, are necessary and sufficient to induce neotenic features of microglia structural maturation through microglia-specific manipulations, and (2) that induction of SRGAP2-dependent neotenic features of microglia maturation impacts the timing of synaptic development in a non-cell autonomous manner. Taken together with previous studies, our results reveal that, during human brain evolution, the human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers in both neurons and microglia.