Biology subjects

Mora-Romero, B.

Publications and source records attributed to Mora-Romero, B..

3 recordsLinked to original sources

bioRxiv2026

Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We hereby demonstrate a new role of hypothalamic microglia in controlling the HPG axis through Rank signaling, a pathway known for its role in bone and mammary gland biology. Whole-body and microglia Rank depletion leads to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) function. In addition, we identify rare gene variants of RANK in patients with HH. Transcriptional profiling upon pubertal Rank loss reveals defective microglia activation and morphological alterations in the median eminence (ME), decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH responses to kisspeptin. Overall, our data uncovers the crucial role of microglia in regulating GnRH function through Rank signaling, with implications for reproductive maturation and fertility. One-Sentence SummaryMicroglia regulates GnRH function through RANK signaling

cell biology↗

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2024

The PHD3-FOXO3 axis modulates the interferon type I response in microglia aggravating Alzheimer's disease progression

Microglia respond to Alzheimers disease (AD) with a variety of transcriptional responses. However, the regulation of specific transcriptional signatures and the contribution of each individual response to disease progression is only starting to be characterized. We have previously shown that hypoxia via hypoxia inducible factor 1 (HIF1) is a strong regulator of A{beta} plaque-associated microglia (A{beta}AM). Here, we characterize the role of HIF1-mediated transcription of Egln3, encoding for PHD3, in A{beta}AM. We show that oligomeric A{beta} treatment (oA{beta}) in vitro induces the expression of Hif1a and Egln3 in microglia, which correlates with the transcriptional activation of genes involved in the interferon type I signature (IFNS) in a PHD3-dependent manner. Mechanistically, we demonstrate FOXO3 to be an important repressor of IFNS in microglia, whose abundance decreases upon A{beta} presence, and, correspondingly, both in human single-nucleus (sn) and mouse A{beta}AM transcriptomics, FOXO3 DNA binding sites define the IFNS. FOXO3 repression of the IFNS is dependent on PHD3, with our results suggesting a physical interaction between both proteins in vitro. In vivo, loss of PHD3 correlate with abrogation of the IFNS and activation of the disease-associated microglia signature (DAM) in A{beta}AM. Transcriptional changes in microglia associate with increased microglia proximity to A{beta} plaques, augmented phagocytosis of A{beta} by microglia, reduced parenchymal levels of A{beta}, and an increase in small-sized plaques. PHD3 deficiency also reduced the A{beta} plaque-associated neuropathology and rescued behavioural deficits of an AD mouse model. Finally, we also demonstrate that microglial PHD3 overexpression during development in the absence of A{beta} pathology is sufficient to induce the IFNS and to behavioural alterations. Altogether, our data strongly indicate that the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, contributing to the progression of AD.

neuroscience↗