Biology subjects

Cabedo, H.

Publications and source records attributed to Cabedo, H..

5 recordsLinked to original sources

bioRxiv2026

Inflammation-induced epigenetic memory restores oligodendrocyte progenitor cell regenerative capacity in the aged central nervous system

Although remyelination, a central nervous system (CNS) regenerative process mediated by oligodendrocyte progenitor cells (OPCs), takes place in an inflammatory environment the long-term impact of inflammation on OPC remyelination capacity remains unclear. Here, we studied the short- and long-term impact of systemic inflammation on adult OPCs to assess whether transient inflammation triggers enduring chromatin remodelling indicative of inflammatory memory in OPCs. We observed long-lasting epigenetic modifications in response to both lipopolyssaccharide (LPS) and polyinosinic:polycytidylic acid (Poly(I:C)), but only LPS induced a tolerance-like memory. LPS-mediated tolerance-like memory enhanced OPC differentiation after demyelination in aged mice, reducing axonal damage. Our findings reveal OPC epigenetic memory of inflammation as a mechanism by which adult OPCs adapt to inflammatory challenges, which could be harnessed to reduce neuroinflammation and enhance remyelination efficiency in ageing and neurodegenerative diseases.

neuroscience↗

bioRxiv2022

SARM1 detection in oligodendrocytes but not Schwann cells though sarm1/Sarm1 deletion does not perturb CNS nor PNS myelination in zebrafish and mice.

SARM1 is a central regulator of programmed axon death and is required to initiate axon self-destruction after traumatic and toxic insults to the nervous system. Abnormal activation of this axon degeneration pathway is increasingly recognized as a contributor to human neurological disease and SARM1 knockdown or inhibition has become an attractive therapeutic strategy to preserve axon loss in a variety of disorders of the peripheral and central nervous system. Despite this, it remains unknown whether Sarm1/SARM1 is present in myelinating glia and whether it plays a role in myelination in the PNS or CNS. It is important to answer these questions to understand whether future therapies inhibiting SARM1 function may have unintended deleterious impacts on myelination. Here we show that Sarm1 mRNA is present in oligodendrocytes in zebrafish but only detectable at low levels in Schwann cells in both zebrafish and mice. We find SARM1 protein is readily detectable in murine oligodendrocytes in vitro and in vivo and activation of endogenous SARM1 in oligodendrocytes induces cell death. In contrast, SARM1 protein is not detectable in Schwann cells and satellite glia in the adult murine nervous system. Cultured Schwann cells contain negligible functional SARM1 and are insensitive to specific SARM1 activators. Using zebrafish and mouse Sarm1 mutants, we show that SARM1 is not required for initiation of myelination nor myelin sheath maintenance by oligodendrocytes and Schwann cells. Thus, strategies to inhibit SARM1 function in the nervous system to treat neurological disease are unlikely to perturb myelination in humans. Main PointsO_LISARM1 protein is detectable in oligodendrocytes but not in Schwann cells C_LIO_LIOligodendrocytes but not Schwann cells die in response to endogenous SARM1 activation C_LIO_LICNS nor PNS myelination, in zebrafish and mice, is hindered by loss of sarm1/Sarm1 C_LI

neuroscience↗

bioRxiv2021

A genetic compensatory mechanism regulated by c-Jun and Mef2d modulates the expression of distinct class IIa HDACs to ensure peripheral nerve myelination and repair

The class IIa histone-deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express HDAC4, 5 and 7 but not HDCA9. Here we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when HDAC4 and 5 are knocked-out from Schwann cells, a c-Jun dependent mechanism induces the compensatory overexpression of HDAC7 permitting, although with a delay, the formation of a myelin sheath. When HDAC4,5 and 7 are simultaneously removed, the Myocyte- specific enhancer-factor d (Mef2d) binds to the promoter and induces the de novo expression of HDAC9, and although several melanocytic- lineage genes are mis- expressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa HDAC family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.

cell biology↗

bioRxiv2020

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.

neuroscience↗

bioRxiv2018

A Fasciclin 2 functional switch controls organ size in Drosophila

How cell to cell interactions control local tissue growth to attain a species-specific pattern and organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2 (Drosophila NCAM), is expressed during the development of neural and epithelial organs. Genetic mosaic analysis of Fasciclin 2 reveals two complementary and opposing functions during imaginal disc growth, a cell autonomous requirement to promote growth and an opposite non-cell autonomous function to restrain growth at high expression levels. This non-cell autonomous function is mediated by the Fasciclin 2 heterophilic-binding partners CG15630 and CG33543. We show that EGFR physically interacts with Fasciclin 2 and mediates both the cell autonomous and the non-cell autonomous function. We further show that EGFR activity in turn promotes the cell autonomous expression of Fasciclin 2. We suggest that the auto-stimulatory loop between EGFR and Fasciclin 2 operates until reaching a threshold where the Fasciclin 2 non-cell autonomous function counteracts the growth-promoting activity of the homophilic interaction to terminate imaginal disc growth. Accordingly, we have found that Fasciclin 2 limits imaginal disc growth by the end of larval development. Cellular integration of Fasciclin 2 autonomous and non-cell autonomous signaling from neighbor cells may be a key regulator component to orchestrate the rate of intercalary cell proliferation and the final size of an organ.\n\nAuthor SummaryOne of the key unsolved problems in Biology is how a species-specific size is attained during animal development. During development cells should compute the amount of intercalary tissue growth to stop cell proliferation when reaching a correct pattern and size. Classic studies demonstrated that local cell interactions are key in controlling organ growth to reach a correct size and pattern in vertebrates and invertebrates. We present evidence strongly suggesting that Fasciclin 2 (the ortholog of NCAM in Drosophila) functions as a growth level switch to control pattern and organ size. First, we use genetic mosaic analyses to show that Fasciclin 2 promotes organ growth in a cell autonomous manner. Then we show that Fasciclin 2 restrains growth at high expression levels in a non-cell autonomous manner, and that there is a requirement for Fasciclin 2 to limit growth by the end of larval development. This function is dependent on Fasciclin 2 heterophilic binding partners CG15630 and CG33543. The Epidermal Growth Factor receptor mediates both functional facets of Fasciclin 2 and its activity in turn increases Fasciclin 2 cell autonomous expression, suggesting the existence of a functional auto-stimulatory loop. We also show that the Epidermal Growth Factor receptor and Fasciclin 2 physically interact. Our results show that the amount of Fasciclin 2 between cells determines organ size by acting as an expression level switch for EGFR function, and suggest that other specific CAM interactions may integrate similar expression level switches acting as a code for cells to compute local growth in attaining a species-specific organ size and shape.

developmental biology↗