- Lineage transcription factors PU.1, IRF8, RUNX1 shape chromatin accessibility, priming microglia for environmental responsiveness and developmental specialisation.
- Brain trophic factors CSF1, IL-34, TGF-β and peripheral cues cooperate via transcriptional complexes, notably SMADs with SALL1, to stabilise or redirect identity.
- State dependent programming during sensitive windows leaves epigenetic marks; insults like maternal immune activation increase risk for ASD, ADHD and schizophrenia.
Cell Mol Neurobiol. 2026 May 11. doi: 10.1007/s10571-026-01741-7. Online ahead of print.
ABSTRACT
Microglia, the resident immune cells of the central nervous system, have emerged as dynamic architects of brain development and homeostasis. Here, we propose a unifying framework of “Genetic-Environmental Programming” to explain how microglial identity emerges through the bidirectional convergence of lineage-intrinsic factors and spatiotemporally patterned extrinsic signals. This programming process operates through three core principles. First, lineage-determining transcription factors (PU.1, IRF8, RUNX1) establish chromatin accessibility landscapes that confer responsiveness to environmental cues. Second, brain-derived trophic factors (CSF1, IL-34, TGF-β) and peripheral inputs (microbiota metabolites, adaptive immune signals) stabilize or redirect these intrinsic programs through cooperative transcriptional complexes-notably, TGF-β signaling through SMADs converges with the microglia-specific transcription factor SALL1 to sustain homeostatic identity. Third, programming outcomes are state-dependent, with early configurations constraining but not absolutely determining later states. This framework enables context-specific microglial specialization for neurodevelopmental tasks while maintaining developmental plasticity. Importantly, this programming is vulnerable during sensitive developmental windows; environmental insults-including maternal immune activation, prenatal stress, and postnatal inflammation-can disrupt normal programming through lasting epigenetic modifications, impairing microglial immune and synaptic functions. Such misprogramming establishes a developmentally encoded vulnerability to neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and schizophrenia. Understanding microglial identity as a programmed continuum-rather than a predetermined fate-shifts therapeutic strategies from broad immunomodulation toward precise reprogramming of developmental checkpoints.
PMID:42113313 | DOI:10.1007/s10571-026-01741-7
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