Work

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

Year: 2026

Type: article

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.

Source: Cellular and Molecular Neurobiology

DOI: 10.1007/s10571-026-01741-7

Authors: YanXiang Zhang, Mengxuan Yang, Simin Yang, Sheng Zhang

Institutions: Nanfang Hospital, Southern Medical University, Zhujiang Hospital

Language: English

Topic: Neuroinflammation and Neurodegeneration Mechanisms

Subfield: Neurology

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,590