Biology subjects

yi, c.

Publications and source records attributed to yi, c..

3 recordsLinked to original sources

bioRxiv2026

Nuclear Cx43 restrains microglial neurotoxicity during brain development

Microglia are essential for sculpting the developing brain, yet the molecular mechanisms that select beneficial overreactive phagocytosis remain incompletely understood. Connexin 43 (Cx43, encoded by GJA1 in humans) is best known as a gap junction and hemichannel protein, although its non-canonical, channel-independent functions are increasingly recognized. We found that Cx43 is highly expressed in microglia during the perinatal period in human and mouse, whereas proportion of full-length multimeric Cx43 unexpectedly localizes to the nucleoplasm. Deletion of microglial Cx43 in mice during development instigates a transient neurotoxic state with microgliosis, upregulated phagocytic and complement pathways, excessive neuronal apoptosis, translating into depressive-like and cognitive deficits in the adulthood. Notably, neither microglia-specific deletion of Cx43 in adulthood nor hemichannel blockade recapitulate these changes, indicating a channel-independent, developmental stage-specific neuroprotective mechanism. Nucleus-targeted Cx43 overexpression suppresses neurotoxic markers and neural apoptosis. Nuclear Cx43 interacts with transcriptional regulators to restrain proinflammatory gene programs, nuclear import of Cx43 is driven by neurogenic niche-derived bFGF, which triggers AKT-mediated phosphorylation of a C-terminal nucleus localization signal (NLS), 14-3-3 binding, and importin-dependent nucleus translocation. These findings reveal a developmentally restricted nuclear Cx43 function that restrains microglial neurotoxicity while promoting microglial physiological functions thus expanding connexin biology to transcriptional co-regulation and pointing to a potential avenue for therapeutic intervention.

neuroscience↗

bioRxiv2026

Age-Associated Remodeling of neuroglial Connexin43 in the Mouse and Human Brain

Age-dependent changes in the major neuroglial junctional channel Connexin43 (Cx43) are poorly defined. We integrated public multi-organ and single-cell datasets with high-resolution morphological, biochemical, and functional analyses of human and mouse brains. We reveal a non-linear aging trajectory for Cx43, marked by an adaptational midlife elevation followed by a late-life decline. These molecular changes proceed in the absence of significant cell loss but are associated with extensive glial remodeling. Notably, while astrocytic gap junction coupling in the hippocampus remains largely preserved, aging induces a selective increase in hemichannel mediated dye uptake in both microglia and hippocampal astrocytes. In human cortical and hippocampal tissues, we confirm that aging drives a significant reduction in astrocytic Cx43 expression, alongside characteristic morphological simplification of cell structure and domain contraction. Together, our findings redefine the aging brain as a state of active, multi-level glial remodeling rather than a simple decline in connexin-mediated communication.

neuroscience↗

bioRxiv2024

Astrocyte ezrin defines resilience to stress-induced depressive behaviours in mice

Astrocyte atrophy is the main histopathological hallmark of major depressive disorder (MDD) in humans and in animal models of depression. Here we demonstrated that manipulating with ezrin expression specifically in astrocytes significantly increases the resilience of mice to chronic unpredictable mild stress (CUMS). Overexpression of ezrin in astrocytes from prefrontal cortex (PFC) rescued depressive-like behaviours induced by CUMS, whereas down-regulation of ezrin in astrocytes from PFC increased mice susceptibility to CUMS and promoted depressive-like behaviours. These behavioural changes correlated with astrocytic morphology. Astrocytes from PFC of mice sensitive to CUMS demonstrated significant atrophy; similar atrophy was found in astrocytes from animals with down-regulated ezrin expression. To the contrary morphology remains unchanged astrocytes in animals resistant to CUMS and in animals with astrocytic overexpression of ezrin. Morphological changes also correlated with ezrin immunoreactivity which was low in mice with depressive-like behaviours and high in mice resistant to stress. We conclude that Ezrin-dependent morphological remodelling of astrocytes defines the sensitivity of mice to stress: high ezrin expression renders them stress resilient, whereas low ezrin expression promotes depressive-like behaviour in response to chronic stress.

neuroscience↗