Despite recent progress, the complex roles played by the extracellular matrix in development and disease are still far from being fully understood. Here, we took advantage of the zebrafish sly mutation which affects Laminin γ1, a major component of basement membranes, to explore its role in the development of the olfactory system. Following a detailed characterisation of Laminin distribution in the developing olfactory circuit, we analysed basement membrane integrity, olfactory placode and brain morphogenesis, and olfactory axon development in sly mutants, using a combination of immunochemistry, electron microscopy and quantitative live imaging of cell movements and axon behaviours. Our results point to an original and dual contribution of Laminin γ1-dependent basement membranes in organising the border between the olfactory placode and the adjacent brain: they maintain placode shape and position in the face of major brain morphogenetic movements, they establish a robust physical barrier between the two tissues while at the same time allowing the local entry of the sensory axons into the brain and their navigation towards the olfactory bulb. This work thus identifies key roles of Laminin γ1-dependent basement membranes in neuronal tissue morphogenesis and axon development in vivo.

Despite recent progress, the complex roles played by the extracellular matrix in development and disease are still far from being fully understood. Here, we took advantage of the zebrafish sly mutation which affects Laminin γ1, a major component of basement membranes, to explore its role in the development of the olfactory system. Following a detailed characterisation of Laminin distribution in the developing olfactory circuit, we analysed basement membrane integrity, olfactory placode and brain morphogenesis, and olfactory axon development in sly mutants, using a combination of immunochemistry, electron microscopy and quantitative live imaging of cell movements and axon behaviours. Our results point to an original and dual contribution of Laminin γ1-dependent basement membranes in organising the border between the olfactory placode and the adjacent brain: they maintain placode shape and position in the face of major brain morphogenetic movements, they establish a robust physical barrier between the two tissues while at the same time allowing the local entry of the sensory axons into the brain and their navigation towards the olfactory bulb. This work thus identifies key roles of Laminin γ1-dependent basement membranes in neuronal tissue morphogenesis and axon development in vivo.

Despite recent progress, the complex roles played by the extracellular matrix in development and disease are still far from being fully understood. Here, we took advantage of the zebrafish sly mutation which affects Laminin γ1, a major component of basement membranes, to explore its role in the development of the olfactory system. Following a detailed characterisation of Laminin distribution in the developing olfactory circuit, we analysed basement membrane integrity, olfactory placode and brain morphogenesis, and olfactory axon development in sly mutants, using a combination of immunochemistry, electron microscopy and quantitative live imaging of cell movements and axon behaviours. Our results point to an original and dual contribution of Laminin γ1-dependent basement membranes in organising the border between the olfactory placode and the adjacent brain: they maintain placode shape and position in the face of major brain morphogenetic movements, they establish a robust physical barrier between the two tissues while at the same time allowing the local entry of the sensory axons into the brain and their navigation towards the olfactory bulb. This work thus identifies key roles of Laminin γ1-dependent basement membranes in neuronal tissue morphogenesis and axon development in vivo .

Adenylyl Cyclase 8E (AC8E), which lacks part of M1 transmembrane domain, has been previously shown to dimerize with AC3 and down-regulate its activity, but the molecular mechanism of this inhibitory effect has remained elusive. Here, we first show that AC8E also inhibits AC2 and AC6, highlighting the functional importance of this novel regulatory mechanism in the cAMP signaling pathway across AC families. We then completed the partial structure of Bos taurus AC9 using combinations of comparative modeling and fold recognition methods, and used this as a template to build the first full 3D-models of AC8 and AC8E. These models evidenced that the lack of M1 transmembrane domain of AC8E shifts the N-terminal domain, which impacts the orientation of the helical domains, thus affecting the catalytic site. This was confirmed in living cells with cAMP imaging, where we showed that the N-terminal domain is required for reducing cAMP production. Our data also show that AC8E prevents the translocation of other ACs towards the plasma membrane, further reducing the cAMP responsiveness to extracellular signals. This newly discovered dual inhibitory mechanism provides an additional level of regulation of cAMP-dependent signals integration.

AbstractWhile the role of the immune system in multiple sclerosis (MS) is widely acknowledged, our comprehension of the transcriptional foundations of this prevalent neurological disorder remains largely incomplete. Here, we conducted high-depth RNA sequencing on monocytes from a cohort of patients with MS to explore rare RNA species associated with the disease. In a subset of the patients, a markedly altered transcriptome was observed, coinciding with a decreased expression of the epigenetic silencer HP1α/CBX5. These patients also exhibited diminished expression of multiple genes encoding subunits of the Integrator complex. Alongside, there were clear indications of decreased Integrator activity, including impaired U snRNA and enhancer-RNA maturation/degradation and dysregulated RNA polymerase II (RNAPII) pause-release. Inactivation of Cbx5 in the mouse recapitulated the defects in Integrator activity and resulted in hypersensitivity to Experimental Autoimmune Encephalomyelitis (EAE). While these data implied an unexpected function for HP1α in regulating RNAPII pause-release, they also showed that the dysregulation of numerous genes in MS patients could be adributed to either the biased distribution of transcription toward the 5’ end of genes or the heightened elongation and stability of enhancer RNAs. We therefore propose that impaired Integrator activity, which has been hinted at by mutations within Integrator subunits previously linked to an increased risk of MS, can provide a well-defined mechanistic understanding of the transcriptional anomalies associated with the disease.

A number of genetic variants in the SYNM gene encoding for the intermediate filament synemin have been reported in patients with cardiomyopathies, skeletal myopathies, cancer and certain neurodegenerative disorders. To better understand its role, we generated a human induced pluripotent stem cell line with a homozygous deletion in the SYNM gene by CRISPR/Cas9 genome editing. The synemin-knockout human induced pluripotent stem cells exhibit typical morphology of pluripotent cells, expression of pluripotency markers, normal karyotype and differentiation capacity in the three germ layers. This line will allow us to investigate the role of synemin in cardiomyopathy upon differentiation into beating cardiomyocytes.

Neurological and psychiatric diseases generally have no cure, so innovative non-pharmacological treatments, including non-invasive brain stimulation, are interesting therapeutic tools as they aim to trigger intrinsic neural repair mechanisms. A common brain stimulation technique involves the application of pulsed magnetic fields to affected brain regions. However, investigations of magnetic brain stimulation are complicated by the use of many different stimulation parameters. Magnetic brain stimulation is usually divided into two poorly connected approaches: (1) clinically used high-intensity stimulation (0.5-2 Tesla, T) and (2) experimental or epidemiologically studied low-intensity stimulation (μT-mT). Human tests of both approaches are reported to have beneficial outcomes, but the underlying biology is unclear, and thus optimal stimulation parameters remain ill defined. Here, we aim to bring together what is known about the biology of magnetic brain stimulation from human, animal, and in vitro studies. We identify the common effects of different stimulation protocols; show how different types of pulsed magnetic fields interact with nervous tissue; and describe cellular mechanisms underlying their effects-from intracellular signalling cascades, through synaptic plasticity and the modulation of network activity, to long-term structural changes in neural circuits. Recent advances in magneto-biology show clear mechanisms that may explain low-intensity stimulation effects in the brain. With its large breadth of stimulation parameters, not available to high-intensity stimulation, low-intensity focal magnetic stimulation becomes a potentially powerful treatment tool for human application.

Despite recent progress, the complex roles played by the extracellular matrix in development and disease are still far from being fully understood. Here, we took advantage of the zebrafish sly mutation which affects Laminin γ1, a major component of basement membranes, to explore its role in the development of the olfactory system. Following a detailed characterisation of Laminin distribution in the developing olfactory circuit, we analysed basement membrane integrity, olfactory placode and brain morphogenesis, and olfactory axon development in sly mutants, using a combination of immunochemistry, electron microscopy and quantitative live imaging of cell movements and axon behaviours. Our results point to an original and dual contribution of Laminin γ1-dependent basement membranes in organising the border between the olfactory placode and the adjacent brain: they maintain placode shape and position in the face of major brain morphogenetic movements, they establish a robust physical barrier between the two tissues while at the same time allowing the local entry of the sensory axons into the brain and their navigation towards the olfactory bulb. This work thus identifies key roles of Laminin γ1-dependent basement membranes in neuronal tissue morphogenesis and axon development in vivo .

Maintenance of the highly organized striated muscle tissue requires a cell-wide dynamic network through protein-protein interactions providing an effective mechanochemical integrator of morphology and function. Through a continuous and complex trans-cytoplasmic network, desmin intermediate filaments ensure this essential role in heart and in skeletal muscle. Besides their role in the maintenance of cell shape and architecture (permitting contractile activity efficiency and conferring resistance towards mechanical stress), desmin intermediate filaments are also key actors of cell and tissue homeostasis. Desmin participates to several cellular processes such as differentiation, apoptosis, intracellular signalisation, mechanotransduction, vesicle trafficking, organelle biogenesis and/or positioning, calcium homeostasis, protein homeostasis, cell adhesion, metabolism and gene expression. Desmin intermediate filaments assembly requires αB-crystallin, a small heat shock protein. Over its chaperone activity, αB-crystallin is involved in several cellular functions such as cell integrity, cytoskeleton stabilization, apoptosis, autophagy, differentiation, mitochondria function or aggresome formation. Importantly, both proteins are known to be strongly associated to the aetiology of several cardiac and skeletal muscles pathologies related to desmin filaments disorganization and a strong disturbance of desmin interactome. Note that these key proteins of cytoskeleton architecture are extensively modified by post-translational modifications that could affect their functional properties. Therefore, we reviewed in the herein paper the impact of post-translational modifications on the modulation of cellular functions of desmin and its molecular chaperone, the αB-crystallin.

Magnetoreception, the remarkable ability of organisms to perceive and respond to Earth's magnetic field, has captivated scientists for decades, particularly within the field of quantum biology. In the plant science, the exploration of the complicated interplay between quantum phenomena and classical biology in the context of plant magnetoreception has emerged as an attractive area of research. This comprehensive review investigates into three prominent theoretical models: the Radical Pair Mechanism (RPM), the Level Crossing Mechanism (LCM), and the Magnetite-based MagR theory in plants. While examining the advantages, limitations, and challenges associated with each model, this review places a particular weight on the RPM, highlighting its well-established role of cryptochromes and in-vivo experiments on light-independent plant magnetoreception. However, alternative mechanisms such as the LCM and the MagR theory are objectively presented as convincing perspectives that permit further investigation. To shed light on these theoretical frameworks, this review proposes experimental approaches including cutting-edge experimental techniques. By integrating these approaches, a comprehensive understanding of the complex mechanisms driving plant magnetoreception can be achieved, lending support to the fundamental principle in the RPM. In conclusion, this review provides a panoramic overview of plant magnetoreception, highlighting the exciting potential of quantum biology in unraveling the mysteries of magnetoreception. As researchers embark on this captivating scientific journey, the doors to deciphering the diverse mechanisms of magnetoreception in plants stand wide open, offering a profound exploration of nature's adaptations to environmental cues.