Biology subjects

Karadottir, R. T.

Publications and source records attributed to Karadottir, R. T..

6 recordsLinked to original sources

bioRxiv2026

Fatty acid binding protein-8 (FABP8/PMP2) reveals molecular heterogeneity of myelin sheaths in the human CNS

Myelin is classically viewed as a uniform axon-insulating membrane, yet its molecular composition may differ between species and even within one species. Fatty acid binding protein-8 (FABP8/PMP2) was previously identified in CNS myelin of humans but not mice. Here we show that FABP8/PMP2 is a defining feature of CNS myelin in humans and old-world-monkeys, but absent from CNS myelin in other mammals, indicating evolutionary neofunctionalization of this lipid-binding protein in the primate lineage. In the human CNS, FABP8/PMP2 marks a subset of myelin sheaths that preferentially ensheath large-diameter axons, revealing sheath-to-sheath molecular heterogeneity correlated with axonal geometry. Chromatin is accessible at the PMP2/Pmp2 gene locus in oligodendrocytes of humans but not mice. Human oligodendrocytes intrinsically express FABP8/PMP2 when transplanted into mouse brains, demonstrating species-specific competence independent of environmental cues. Humanized transgenic mice expressing FABP8/PMP2 in oligodendrocytes form morphologically normal but developmentally transiently thicker myelin sheaths, and show elevated cholesterol content in purified myelin. Because FABP8/PMP2 binds cholesterol, we propose that its emergence in primate CNS myelin contributes to the cholesterol enrichment of human myelin. Thus, CNS myelin protein composition is evolvable and modular, with relevance for myelin lipids and morphology, and previously unrecognized complexity in neuron-glia co-adaptation. Main points- Fatty acid binding protein 8 (FABP8/PMP2) is present in CNS myelin of humans and old-world monkeys - PMP2 defines sheath-to-sheath heterogeneity in the human CNS - PMP2-immunopositive myelin ensheaths large-diameter axons - Human oligodendrocytes intrinsically express PMP2 upon transplantation into mice - Humanized PMP2-transgenic mice show thicker myelin and altered myelin lipid composition

neuroscience↗

bioRxiv2026

Myelin basic protein is an RNA chaperone in microglial nuclear retro-transport

CNS oligodendrocytes generate myelin, an RNA-containing proteolipid substance that enhances axonal transmission. In multiple sclerosis (MS), myelin debris is phagocytosed by microglia (MG), and prior studies have detected myelin-derived mRNA in MG nuclei, suggesting a retrograde transport pathway. We report myelin basic protein (MBP) is a nucleic acid-binding and trafficking protein. We found that retro-transport of myelin RNA into the MG nucleus was phagocytosis and importin-dependent. Transcriptomic and proteomic analyses of MG nuclei revealed enrichment of myelin mRNAs and proteins, with MBP singularly detected in soluble and chromatin-associated fractions. MBP bound mRNA with high affinity (Kd {approx} 0.30 nM) and was sufficient to facilitate MG RNA nuclear import in vitro and in vivo. Functionally, MBP mediated the delivery of small interfering RNAs for targeted knockdown of toll-like receptor 4. These findings indicate MBP as an RNA-binding protein capable of MG nuclear import, providing insight into neuroinflammatory pathology of MS.

neuroscience↗

bioRxiv2025

Constitutive DREADD signalling modulates oligodendrocyte precursor cell bioelectrical membrane properties and fate

Oligodendrocyte precursor cells (OPCs) are small cells in the central nervous system that proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for myelin plasticity and repair. G protein-coupled neuromodulator receptors can regulate OPC fate, but the role of individual G protein families is unclear. Here, we use chemogenetics to directly investigate the role of Gq and Gi proteins in OPC fate. We find that expressing the DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) hM3Dq or hM4Di in OPCs without activating them with designer agonists induces constitutive G protein signalling, which alters bioelectrical membrane properties such as voltage-gated ion channels and glutamate receptors in OPCs. Further, we find that hM3Dq or hM4Di expression alone modulates OPC fate, increasing or decreasing differentiation, respectively, suggesting that directly targeting G protein signalling can be used to bidirectionally regulate differentiation. Importantly, our data raise a note of caution regarding the use of DREADDs in both excitable and non-excitable small cells. SIGNIFICANCE STATEMENTDesigner Receptors Exclusively Activated by Designer Drugs (DREADDs) are widely used to manipulate neuronal excitability. Their use in other neural cell types is rapidly increasing; however, DREADDs have not been thoroughly characterized in non-neuronal cells. Here, we show that when expressed in small excitable cells like oligodendrocyte precursor cells, DREADDs are constitutively active, unlike in excitatory neurons. This constitutive DREADD signalling alters cell fate and bioelectrical membrane properties like voltage-gated ion channels and glutamate receptors. Our data highlight that constitutive DREADD activity represents a significant confound that needs to be considered and controlled for when expressing DREADDs in small cells, and demonstrate that G protein signalling is a potent regulator of OPC fate, with a potential for therapeutic implications.

neuroscience↗

bioRxiv2024

Substrate stiffness regulates neuronal maturation via Piezo1-mediated TTR activity

During brain development, neurons extend axons to connect to their target cells while initiating a maturation process during which neurons start expressing voltage-gated ion channels, form synapses, express synaptic transmitters and receptors, and start communicating via action potentials. Little is known about external factors regulating this process. Here, we identified environmental mechanics as an important regulator of neuronal maturation, and a molecular pathway linking tissue stiffness to this process. Using patch clamp electrophysiology, calcium imaging and immunofluorescence, we found that neurons cultured on stiffer substrates showed a delay in voltage-gated ion channel activity, spontaneous and evoked action potentials, and synapse formation. RNA sequencing and CRISPR/Cas9 knockdown revealed that the mechanosensitive ion channel Piezo1 supresses transthyretin (TTR) expression on stiffer substrates, slowing down synapse formation and consequently electrical maturation. In agreement, the stiffness of developing Xenopus laevis brain negatively correlated with local synapse densities, and stiffening of brain tissue resulted in a significant delay of synaptic activity in vivo. Our data indicate that environmental stiffness represents a fundamental regulator of neuronal maturation, which is important for the development of normal circuitry in the brain, and potentially for neurodevelopmental disorders. Furthermore, the mechanical regulation of TTR downstream of Piezo1 may be found in many other biological systems.

developmental biology↗

bioRxiv2021

Activity-dependent alteration of early myelin ensheathment in a developing sensory circuit

Adaptive myelination has been reported in response to experimental manipulations of neuronal activity, but the links between sensory experience, corresponding neuronal activity, and resultant alterations in myelination require investigation. To study this, we used the Xenopus laevis tadpole, which is a classic model for studies of visual system development and function because it is translucent and visually responsive throughout the formation of this retinotectal system. Here, we report the timecourse of early myelin ensheathment in the Xenopus retinotectal system using immunohistochemistry of myelin basic protein (MBP) along with third-harmonic generation (THG) microscopy, a label-free structural imaging technique. Characterization of the myelination progression revealed an appropriate developmental window to address the effects of early patterned visual experience on myelin ensheathment. To alter patterned activity, we showed tadpoles stroboscopic stimuli and measured the calcium responses of retinal ganglion cell axon terminals. We identified strobe frequencies that elicited robust versus dampened calcium responses, reared animals in these strobe conditions for 7 d, and subsequently observed differences in the amount of early myelin ensheathment at the optic chiasm. This study provides evidence that it is not just the presence but also to the specific temporal properties of sensory stimuli that are important for myelin plasticity.

neuroscience↗

bioRxiv2017

Gene editing in rat embryonic stem cells to produce in vitro models and in vivo reporters

Rat embryonic stem (ES) cells offer the potential for sophisticated genome engineering in this valuable biomedical model species. However, germline transmission has been rare following conventional homologous recombination and clonal selection. Here we used the CRISPR/Cas9 system to target genomic mutations and insertions. We first evaluated utility for directed mutagenesis and recovered clones with biallelic deletions in Lef1. Mutant cells exhibited reduced sensitivity to glycogen synthase kinase 3 inhibition during self-renewal. We then generated a non-disruptive knock-in of DsRed at the Sox10 locus. Two clones produced germline chimaeras. Comparative expression of DsRed and Sox10 validated the fidelity of the reporter. To illustrate utility, oligodendrocyte lineage cells were visualised by live imaging of DsRed in neonatal brain slices and subjected to patch clamp recording. Overall these results show that CRISPR/Cas9 gene editing technology in germline competent rat ES cells is enabling for in vitro studies and for generating genetically modified rats.

developmental biology↗