Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality.

Unlabelled: BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection.

Ablation of cytoskeletal scaffolding proteins, Band 4.1B and Whirlin, leads to cerebellar purkinje axon pathology and motor dysfunction.

The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias.

mTORC1 Activation by Loss of in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization.

Mutations in human tuberous sclerosis complex (TSC) genes and are the leading causes of developmental brain abnormalities and large tumors in other tissues. Murine have been shown to negatively regulate the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in most tissues, and this pathway has been shown to be essential for proper oligodendrocytes/Schwann cell differentiation and myelination. Here, we report that ablation of gene specifically in oligodendrocytes/Schwann cells activates mTORC1 signaling resulting in severe motor disabilities, weight loss, and early postnatal death.

Reorganization of Destabilized Nodes of Ranvier in β Mutants Uncovers Critical Timelines for Nodal Restoration and Prevention of Motor Paresis.

Disorganization of nodes of Ranvier is associated with motor and sensory dysfunctions. Mechanisms that allow nodal recovery during pathological processes remain poorly understood. A highly enriched nodal cytoskeletal protein βIV spectrin anchors and stabilizes the nodal complex to actin cytoskeleton.

Myelination of Purkinje axons is critical for resilient synaptic transmission in the deep cerebellar nucleus.

The roles of myelin in maintaining axonal integrity and action potential (AP) propagation are well established, but its role in synapse maintenance and neurotransmission remains largely understudied. Here, we investigated how Purkinje axon myelination regulates synaptic transmission in the Purkinje to deep cerebellar nuclei (DCN) synapses using the Long Evans Shaker (LES) rat, which lacks compact myelin and thus displays severe locomotion deficits. DCN neurons fired spontaneous action potentials (APs), whose frequencies were dependent on the extent of myelin.

Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy.

Bidirectional interactions between neurons and myelinating glial cells result in formation of axonal domains along myelinated fibers. Loss of axonal domains leads to detrimental consequences on nerve structure and function, resulting in reduced conductive properties and the diminished ability to reliably transmit signals to the targets they innervate. Thus, impairment of peripheral myelinated axons that project to the surface of muscle fibers and form neuromuscular junction (NMJ) synapses leads to muscle dysfunction.

Postnatal Loss of Neuronal and Glial Neurofascins Differentially Affects Node of Ranvier Maintenance and Myelinated Axon Function.

Intricate molecular interactions between neurons and glial cells underlie the creation of unique domains that are essential for saltatory conduction of action potentials by myelinated axons. Previously, the cell surface adhesion molecule Neurofascin (Nfasc) has been shown to have a dual-role in the establishment of axonal domains from both the glial and neuronal interface. While the neuron-specific isoform of Neurofascin (NF186) is indispensable for clustering of voltage-gated sodium channels at nodes of Ranvier; the glial-specific isoform of Neurofascin (NF155) is required for myelinating glial cells to organize the paranodal domain.

Early and Late Loss of the Cytoskeletal Scaffolding Protein, Ankyrin G Reveals Its Role in Maturation and Maintenance of Nodes of Ranvier in Myelinated Axons.

The mechanisms that govern node of Ranvier organization, stability, and long-term maintenance remain to be fully elucidated. One of the molecular components of the node is the cytoskeletal scaffolding protein, ankyrin G (AnkG), which interacts with multiple members of the nodal complex. The role of AnkG in nodal organization and maintenance is still not clearly defined as to whether AnkG functions as an initial nodal organizer or whether it functions as a nodal stabilizer after the nodal complex has been assembled.