Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1

Diankun Yu (), Samhita Jain, Andi Wangzhou, Beika Zhu, Wenyuan Shao, Elena J. Coley-O’Rourke, Stacy Florencio, JaeYeon Kim, Jennifer Ja-Yoon Choi, Mercedes F. Paredes, Tomasz J. Nowakowski, Eric J. Huang and Xianhua Piao ()
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Diankun Yu: University of California San Francisco
Samhita Jain: University of California San Francisco
Andi Wangzhou: University of California San Francisco
Beika Zhu: University of California San Francisco
Wenyuan Shao: University of California San Francisco
Elena J. Coley-O’Rourke: University of California San Francisco
Stacy Florencio: University of California San Francisco
JaeYeon Kim: University of California San Francisco
Jennifer Ja-Yoon Choi: University of California San Francisco
Mercedes F. Paredes: University of California San Francisco
Tomasz J. Nowakowski: University of California San Francisco
Eric J. Huang: University of California San Francisco
Xianhua Piao: University of California San Francisco

Nature, 2025, vol. 646, issue 8085, 676-686

Abstract: Abstract GABAergic neurons are essential cellular components of neural circuits. Their abundance and diversity have increased significantly in the human brain, contributing to the expanded cognitive capacity of humans1. However, the developmental mechanism underlying the extended production of GABAergic neurons in the human brain remains elusive. Here we uncovered the microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We showed that microglia are preferentially distributed in the proliferating zone and identified insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the predicted top ligand–receptor pair underlying microglia–progenitor communication in the prenatal hMGE. Using our newly developed neuroimmune hMGE organoids, which mimic the hMGE cytoarchitecture and developmental trajectory, we demonstrated that microglia-derived IGF1 promotes progenitor proliferation and production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem-cell-induced microglia abolish the induced microglia-mediated progenitor proliferation. Together, these findings revealed a previously unappreciated role of microglia-derived IGF1 in promoting the proliferation of neural progenitors and the development of GABAergic neurons in the human brain.

Date: 2025
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DOI: 10.1038/s41586-025-09362-8

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