Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Pereira-Iglesias, M.; Martinson, D.; Falco, C.; Maldonado-Teixido, J.; Gonzalez-Rodriguez, M.; Senovilla-Ganzo, R.; Benito, E.; Beccari, S.; Valero, J.; Mora-Romero, B.; Ballasch, I.; Viguier, S.; Haene, P.; Boettiger, M.; Reisz, J. A.; Manso, Y.; Parkkinen, L.; Aransay, A. M.; Soria, F. N.; D'Alessandro, A.; Soriano, E.; Thion, M.; Garel, S.; Greter, M.; Giralt, A.; Pascual, A.; Garcia-Moreno, F.; Menassa, D. A.; Carrillo, J. A.; Sierra, A.

doi:10.1101/2025.11.03.685577

Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.11.03.685577

Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

View original source ↗Export metadata ↓

Abstract

Early immune perturbations increase the risk of neurodegenerative and neurodevelopmental disorders, yet the mechanisms underlying the maturation of microglia, the resident immune cells of the brain parenchyma, remain poorly defined. Specifically, how proliferation, morphological differentiation, and phagocytosis are coordinated among microglia progenitors as they colonize the embryonic brain remains unclear. Here, we combined mathematical modeling with spatiotemporal analyses of the murine hippocampus and cerebellum from postnatal day 2 (P2) to P60 to reconstruct the trajectory of microglial development. We identified a proliferative-to-quiescent (P/Q) switch around P3/P4 that preceded the acquisition of morphological complexity and efficient phagocytosis and was accompanied by coordinated shifts in cell-cycle dynamics and metabolic state. Strikingly, this P/Q switch was recapitulated in repopulation contexts in mice and in the human fetal brain, where later stages displayed enhanced phagocytic function coupled to reduced proliferation. Perturbing the proliferative phase through pharmacological or genetic disruption of CSF1R signaling impaired subsequent microglial complexity and phagocytosis efficiency, revealing an unexpected reliance of phagocytosis on proliferation-driven colonization. Finally, we show that microglia stepwise maturation during development is associated with chromatin remodeling and driven by the epigenetic regulator Ikaros. Together, these findings uncover the sequential milestones of microglial development, revealing a potential period of early vulnerability and establishing an unexpected linkage between proliferation and phagocytosis essential to understanding how these processes are coordinated in neurodegenerative disorders.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Pereira-Iglesias, M., Martinson, D., Falco, C., Maldonado-Teixido, J., Gonzalez-Rodriguez, M., Senovilla-Ganzo, R., Benito, E., Beccari, S., Valero, J., Mora-Romero, B., Ballasch, I., Viguier, S., Haene, P., Boettiger, M., Reisz, J. A., Manso, Y., Parkkinen, L., Aransay, A. M., Soria, F. N., D'Alessandro, A., Soriano, E., Thion, M., Garel, S., Greter, M., Giralt, A., Pascual, A., Garcia-Moreno, F., Menassa, D. A., Carrillo, J. A., Sierra, A.. 2025-11-04. Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes. https://doi.org/10.1101/2025.11.03.685577

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Same Movements, Different Skills: How Context Shapes Learning in Humans and Neural Networks

What determines whether experiences are integrated into shared representations or split? Motor skill learning offers a revealing test: when two tasks require an identical sequence of movements, both intuition and theory suggest that practice in one should generalize to the other. Yet we find that changing context can make identical movements different skills. In simple recurrent networks trained on the same sequence across contexts, splitting was greatest when strong contextual inputs coincided with a high initial weight scale; neither alone sufficed. Greater representational separation coincided with separate context-specific learning curves. Humans practicing the same finger sequence while alternating between two performance-irrelevant contexts likewise exhibited context-specific curves, rather than the single continuous trajectory observed when practicing in a single context. State-space modeling favored split learning states in humans and very weakly coupled states in the most context-dependent networks. These findings have broader implications for understanding how learning generalizes across contexts.

neuroscience↗

bioRxiv2026

Postpartum resource scarcity reshapes maternal care, offspring prioritization, and the steroid-sensitive medial preoptic area

Parental care requires balancing offspring needs with environmental constraints, yet how resource scarcity alters the organization of maternal responses remains poorly understood. Here, we examined maternal behavior, offspring prioritization, and steroid receptor-associated extracellular matrix organization in postpartum rats exposed to limited bedding and nesting (LBN) or control conditions with ample nesting materials. LBN increased pup-directed and reduced self-directed behaviors but also increased behavioral entropy, a measure of behavioral fragmentation, indicating less predictable caregiving sequences. LBN dams preferentially retrieved male pups first, whereas control dams preferentially retrieved females first. LBN also increased the proportion of pup-investigation time directed toward males compared with controls. In offspring on postnatal day 10, corticosterone was elevated in female but not male LBN pups, a pattern that paralleled the maternal male bias. To identify associated neurobiological changes, we assessed steroid receptors and extracellular matrix organization in the medial preoptic area (mPOA), a key region for maternal behavior. LBN increased numbers of estrogen receptor (ER)- and androgen receptor (AR)-immunoreactive cells, reduced perineuronal net (PNN) abundance, and decreased receptor-positive cell enwrapment. Because PNNs constrain structural plasticity, these findings suggest that the postpartum environment alters the organization of steroid receptor-associated extracellular matrix, potentially modulating experience-dependent plasticity in neurosteroid-sensitive circuits. In sum, LBN increases the levels of maternal engagement while reshaping its temporal organization and allocation, accompanied by selective remodeling of steroid-sensitive preoptic architecture. Therefore, maternal adaptation to adversity may be better understood as changes in caregiving allocation strategies rather than a simple gain or loss of maternal care.

neuroscience↗

bioRxiv2026

The Computational Grammar of Human Behaviour in a Biological Environment

Human behaviour unfolds as an extended stream of spontaneous actions shaped by environmental demands and the agent's goals. The organisation of these actions, situated between setting abstract goals and concrete movement execution, remains poorly characterised. Here, we introduce DynaClade, an unsupervised temporal action segmentation algorithm for human full-body motion capture data, and apply it to freely moving participants navigating ecologically realistic risky foraging environments in virtual reality. DynaClade identifies discrete actions whose kinematic characteristics and spatial distributions correspond to environmental affordances, supporting the validity of the approach. Among these actions, we discovered a hitherto undescribed movement pattern defined by increased body sway without locomotion. Action sequences were highly non-random and showed clear history dependence beyond first-order Markov structure, most of which was explained by a second-order prediction. This higher-order structure was well captured in a hidden Markov model, in which some of the observed actions were associated with more than one latent state. Each of these latent states corresponded to the same action in a distinct action context. These findings suggest that spontaneous human actions are predominantly selected based on the current action and context, rather than following pre-planned or habitually assembled sequences.

neuroscience↗