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Peer-reviewedCC BY-NC-NDNeuron

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

  • Carlos Diaz-Salazar1
  • JaeYeon Kim2
  • Marine Krzisch3
  • Juyoun Yoo4
  • Patricia R. Nano5
  • Aparna Bhaduri5
  • Rudolf Jaenisch6
  • Mercedes Paredes2
  • Franck Polleux7
7 affiliations
  1. 1Department of Neuroscience, Columbia University, New York, NY 10027, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA. Electronic address: [email protected]
  2. 2Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA
  3. 3School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
  4. 4Department of Neuroscience, Columbia University, New York, NY 10027, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
  5. 5Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
  6. 6Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
  7. 7Department of Neuroscience, Columbia University, New York, NY 10027, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA. Electronic address: [email protected]
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Abstract

The human brain is distinguished by unusually prolonged developmental timing, yet the genetic mechanisms coordinating this neoteny across cell types remain incompletely understood. Here, we show that human cortical microglia undergo neotenic structural and transcriptional maturation relative to mouse microglia. We identify SRGAP2B/C, human-specific paralogs of the ancestral SRGAP2A, as the only human-specific gene duplications expressed in human microglia. Using xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that human-specific SRGAP2B/C, previously shown to reduce SRGAP2A protein abundance, are both necessary and sufficient to induce neotenic structural microglial maturation. Our results reveal that neotenic microglial maturation modifies the timing of synaptic development, linking microglial developmental programs to the timing of circuit formation. Together with previous evidence for neuronal SRGAP2A function, our results suggest that the human-specific SRGAP2B/C paralogs coordinated the emergence of neotenic synaptic development by acting in both neurons and microglia during human brain evolution.

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Cite

BibTeXRIS
BibTeX
@article{diazsalazar2026humanspecific,
  title = {{Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development}},
  author = {Carlos Diaz-Salazar and JaeYeon Kim and Marine Krzisch and Juyoun Yoo and Patricia R. Nano and Aparna Bhaduri and Rudolf Jaenisch and Mercedes Paredes and Franck Polleux},
  journal = {Neuron},
  year = {2026},
  month = jul,
  doi = {10.1016/j.neuron.2026.07.007},
  url = {https://doi.org/10.1016/j.neuron.2026.07.007},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development
AU  - Carlos Diaz-Salazar
AU  - JaeYeon Kim
AU  - Marine Krzisch
AU  - Juyoun Yoo
AU  - Patricia R. Nano
AU  - Aparna Bhaduri
AU  - Rudolf Jaenisch
AU  - Mercedes Paredes
AU  - Franck Polleux
PY  - 2026
DA  - 2026/07/28
JO  - Neuron
DO  - 10.1016/j.neuron.2026.07.007
UR  - https://doi.org/10.1016/j.neuron.2026.07.007
AB  - The human brain is distinguished by unusually prolonged developmental timing, yet the genetic mechanisms coordinating this neoteny across cell types remain incompletely understood. Here, we show that human cortical microglia undergo neotenic structural and transcriptional maturation relative to mouse microglia. We identify SRGAP2B/C, human-specific paralogs of the ancestral SRGAP2A, as the only human-specific gene duplications expressed in human microglia. Using xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that human-specific SRGAP2B/C, previously shown to reduce SRGAP2A protein abundance, are both necessary and sufficient to induce neotenic structural microglial maturation. Our results reveal that neotenic microglial maturation modifies the timing of synaptic development, linking microglial developmental programs to the timing of circuit formation. Together with previous evidence for neuronal SRGAP2A function, our results suggest that the human-specific SRGAP2B/C paralogs coordinated the emergence of neotenic synaptic development by acting in both neurons and microglia during human brain evolution.
SN  - 0896-6273
SN  - 1097-4199
ER  -