In a groundbreaking study poised to reshape our understanding of human brain development, researchers have unraveled a novel mechanism by which microglia, the brain’s resident immune cells, regulate neurogenesis in the prenatal human brain. Published in Nature in 2025, this study reveals that microglia control the proliferation of medial ganglionic eminence (MGE) progenitors through insulin-like growth factor 1 (IGF1), providing compelling evidence for a species-specific pathway critical to GABAergic neuron production during early brain formation.
The development of the human medial ganglionic eminence—an embryonic structure giving rise to GABAergic interneurons—is notably influenced by its intricate cellular environment. Previous research largely overlooked the role of microglia, typically associated with immune surveillance, in this context. This new research overturns traditional views, demonstrating that human microglia are far more integral to neural progenitor dynamics than previously understood.
Using neuroimmune human MGE organoids (MGEOs) combined with microglial transplantation, the study meticulously mapped the expression patterns of IGF1 and its receptor IGF1R. They found that microglia uniquely express IGF1, while the neural progenitor radial glia within the MGEOs exhibit high levels of IGF1R, setting the stage for direct signaling interactions. Immunohistochemical analyses confirmed this spatial distribution, reinforcing the hypothesis that microglia-derived IGF1 acts as a paracrine factor promoting progenitor cell proliferation in these developing cortical regions.
The researchers employed an elegant set of functional experiments to elucidate IGF1’s role. MGEOs, cultured either with or without induced microglia, were treated with recombinant human IGF1 protein or IGF1-neutralizing antibodies. Remarkably, IGF1 supplementation rescued progenitor proliferation in organoids devoid of microglia, while neutralizing the factor abolished the proliferative effects typically conferred by microglial transplantation. These results unambiguously pinpointed IGF1 as the critical mediator by which microglia foster interneuron progenitor expansion.
Delving deeper, the team generated IGF1 knockout microglia using CRISPR-Cas9 technology applied to human embryonic stem cells. Transplantation of these IGF1-deficient microglia failed to stimulate MGE progenitor proliferation in MGEOs, a defect that recombinant IGF1 treatment could completely rescue. This genetic validation underscored the indispensable nature of microglial IGF1 in regulating human MGE neurogenesis, providing a robust mechanistic framework.
Interestingly, the study observed that IGF1 knockout did not impact the microglial population’s density, morphology, or distribution within the organoids, indicating that the proliferative effects are due to IGF1’s signaling, rather than microglial presence or migration. Complementary experiments involving IGF1 receptor inhibition—using small molecule inhibitors such as GSK4529 and picropodophyllin—abolished the microglia-induced proliferation, confirming that IGF1 acts through its canonical receptor pathway during this developmental window.
Extending the investigation to cortical organoids, the research team further demonstrated that microglia and microglia-derived IGF1 enhance proliferation among cortical neural progenitor populations marked by PAX6 expression. This finding suggests that microglial IGF1 is a generalizable modulator of neural progenitor proliferation beyond the MGE, potentially influencing diverse neuronal lineages and brain regions during prenatal development.
A fascinating aspect of this study lies in its comparative and evolutionary insights. While IGF1 expression by microglia is well documented in specific mouse brain regions, such as axon tract-associated microglia, the researchers found no detectable IGF1 in the microglia localized to the mouse MGE. Moreover, conditional IGF1 knockout in mouse microglia during embryogenesis did not affect MGE proliferation, highlighting a striking species-specific difference. These observations reinforce the concept that human microglia have evolved unique roles in modulating the developmental dynamics of interneuron progenitors through IGF1 signaling.
This species specificity has profound implications for translational neuroscience and the modeling of human neurodevelopmental disorders. The reliance on rodent systems to infer human brain development may overlook critical pathways such as microglial IGF1 regulation uncovered here. Therefore, human-specific models, such as neuroimmune organoids, prove indispensable for unraveling the nuances of fetal brain maturation and the origins of inhibitory neuron circuitry.
The study also raises intriguing questions about the intersection of immune cells and neural development, placing microglia at the nexus of neuroimmune crosstalk. Given that dysfunctional GABAergic interneuron populations underlie numerous neuropsychiatric conditions, including schizophrenia and autism spectrum disorders, understanding microglial contributions offers promising avenues for therapeutic intervention.
Technically, the use of MGEOs integrated with induced microglia, CRISPR-Cas9 gene editing, and rigorous immunohistochemical quantifications allowed the research team to dissect cellular interactions with unparalleled precision. Their approach provided compelling evidence that IGF1-mediated microglial support is essential in human interneuronal progenitor proliferation, a cornerstone for balanced excitatory-inhibitory dynamics in the cortex.
The identification of IGF1 as a secreted factor by microglia that directly influences radial glial proliferation advances our molecular understanding of human neurogenesis and implicates the neuroimmune axis as a key player. The discovery that microglial IGF1 effects are absent in mice contextualizes the evolutionary divergence in brain development paradigms and underscores the importance of human-specific experimental systems in neurobiology.
In conclusion, this landmark study establishes microglial IGF1 signaling as a pivotal regulator of GABAergic neurogenesis in the prenatal human brain. By revealing a species-specific neuroimmune mechanism, it challenges pre-existing dogma and paves the way for reimagining the cellular choreography underlying brain assembly. The implications for developmental neuroscience, disease modeling, and regenerative medicine are profound, exemplifying how fundamental research can illuminate the complex biology of human brain formation.
Subject of Research: Microglial regulation of neurogenesis in the prenatal human medial ganglionic eminence via IGF1 signaling.
Article Title: Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1.
Article References:
Yu, D., Jain, S., Wangzhou, A. et al. Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1. Nature (2025). https://doi.org/10.1038/s41586-025-09362-8
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