Genetic-Environmental Programming of Microglial Identity: Shaping Spatiotemporal Dynamics in Neurodevelopment and Neurodevelopmental Diseases

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.