Biology subjects

Panic, R.

Publications and source records attributed to Panic, R..

3 recordsLinked to original sources

bioRxiv2026

Development of a Humanized Mouse Model for Studying adult Spinal Cord myelination, remyelination and Drug Efficacy

Oligodendrocytes are essential for central nervous system (CNS) function through their roles in myelination and neuronal support. Remyelination, the regeneration of myelin after damage, often fails in human demyelinating diseases, leading to progressive neurological dysfunction. While the biology of rodent oligodendroglia has been investigated in depth, species-specific differences have hindered the study of human oligodendrocyte progenitor cells maturation using current animal models. To address this gap, we developed a humanized oligodendroglia chimeric mouse model by transplanting human iPSC-derived O4+ oligodendroglial progenitors (hiOLs) into the developing spinal cord of myelin deficient-immunosuppressed mice followed by demyelination of the adult humanized spinal cord. This paradigm allows in vivo investigation of hiOL fate during their maturation and ageing, and the response of their settled progeny to demyelinating injury. Following transplantation during postnatal development, hiOLs proliferated, migrated, and differentiated into mature oligodendrocytes, initiating axonal myelination. A population of undifferentiated, proliferative adult human oligodendrocyte progenitors presisted, indicating a reservoir of these cells capable of responding to injury. Spinal cord focal demyelination via lysolecithin injection in the adult humanized spinal cord led to transient loss of human-derived mature oligodendrocytes and myelin, followed by myelin recovery together with endogenous cells. Treatment with the histamine receptor H3 antagonist, bavisant, a recently identified promyelinating compound, significantly enhanced hiOL maturation and myelin production, indicating promotion of their differentiation when administered post-demyelination. Electron microscopy showed an increased number of human-derived remyelinated axons together with decreased g-ratios in bavisant treated animals. This humanized spinal cord model of myelination/demyelination-remyelination faithfully recapitulates key aspects of human oligodendrocyte biology and CNS repair, providing a powerful tool to study human-specific myelination and remyelination mechanisms and screen for emerging remyelinating therapies. Its application in disease modeling and preclinical testing holds promise for advancing personalized treatments in demyelinating and neurodegenerative disorders.

neuroscience↗

bioRxiv2023

PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the following step of wrapping and expansion of myelin membranes. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for demyelinating diseases and neurodevelopmental disorders. SignificanceRemodeling actin cytoskeleton plays a crucial role in myelin formation by oligodendrocytes (OLs). Recent studies have shown that expansion and wrapping of myelin membranes around axons depends on actin depolymerization. However, the molecular mechanisms triggering this key step in myelination are not fully elucidated. Using genetic and pharmacological tools as well as proteomics analyses, we found that PAK1 (P21 Activated Kinase 1) kinase activity is maintained inhibited by NF2/Merlin in OLs to allow actin depolymerization and, consequently, myelin membrane expansion. Pak1 loss-of-function in OLs leads to an increase in myelin thickness in the white matter of adult mice, confirming the role of PAK1 inactivation in myelin membrane expansion.

neuroscience↗

bioRxiv2022

Gcm: a novel anti-inflammatory transcriptional cascade conserved from flies to humans

Innate immunity is an ancestral process that can induce pro- and anti-inflammatory states. A major challenge is to characterise the transcriptional cascades that modulate the response to chronic and acute inflammatory challenges. The Drosophila melanogaster Gcm transcription factor represents an interesting candidate for its potential anti-inflammatory role. Here we explore its evolutionary conservation and its mode of action. We found that the murine ortholog Gcm2 (mGcm2) is expressed upon aging, which is considered as a state of chronic inflammation. mGcm2 is found in a subpopulation of microglia, the innate immune cells of the central nervous system (CNS). Its expression is also induced by a lyso-phosphatidylcholine (LPC)-induced CNS demyelination (acute inflammation) and mGcm2 conditional knock out mice show an increased inflammatory phenotype upon aging or LPC injection. In agreement with the role of this transcriptional cascade in inflammation, the human ortholog hGCM2 is expressed in active demyelinating lesions of Multiple Sclerosis (MS) patients. Finally, Drosophila gcm expression is induced upon aging as well as during an acute inflammatory response and its overexpression decreases the inflammatory phenotype. Altogether, our data show that the inducible Gcm pathway is highly conserved from flies up to humans and represents a potential therapeutic anti-inflammatory target in the control of the inflammatory response.

neuroscience↗