ROLE OF RETINOID RECEPTORS IN MICROGLIA DIVERSITY AND FUNCTIONS IN BRAIN DEVELOPMENT AND HOMEOSTASIS

Microglia are resident immune cells of the central nervous system, comprising approximately 10% of total brain cells, playing a key role in brain development and adult homeostasis. They are highly dynamic and heterogeneous across developmental stages, brain regions, and pathological conditions. While retinoid signalling is well recognised as critical for vertebrate development and immune cell regulation, its contribution to microglial development and function remains poorly understood.
In this study, we investigated the role of retinoid signalling in microglia and brain homeostasis. Using Cx3cr1-driven Cre recombinase, we generated inducible and constitutive microglia-specific knockout mouse models of Retinoic Acid Receptors (RARα, RARβ, and RARγ). Behavioural assays revealed distinct phenotypes depending on the pre- or post-natal RAR inactivation, ranging from altered cognitive to emotional processing, suggesting that retinoid signalling influences microglial regulation of neuronal circuits and behaviour. Importantly, some of these phenotypes were sex-dependent.
To dissect cellular and molecular mechanisms underlying these phenotypes, we performed scRNA-seq on microglia, revealing population-level changes and shifts in microglial subtypes upon retinoid receptor loss. Whole-brain snRNA-seq further revealed transcriptomic changes in other neural cell types influenced by altered microglial states. Additionally, spatial transcriptomics using the Xenium platform uncovered region-specific transcriptional changes associated with altered neuroinflammatory responses.
Integrating these datasets enabled us to characterise microglial heterogeneity and functional specialisation in a niche-specific context, linking diversity to brain physiology and behavioural outcomes. Together, our findings reveal retinoid receptors are key regulators of microglial diversity and function and highlight potential mechanisms connecting microglial dysfunction to neurodegenerative diseases.