Semaphorin Receptors Antagonize Wnt Signaling Through Beta-Catenin Degradation.

Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells.

Structure and function of Semaphorin-5A glycosaminoglycan interactions.

Integration of extracellular signals by neurons is pivotal for brain development, plasticity, and repair. Axon guidance relies on receptor-ligand interactions crosstalking with extracellular matrix components. Semaphorin-5A (Sema5A) is a bifunctional guidance cue exerting attractive and inhibitory effects on neuronal growth through the interaction with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs), respectively.

Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration.

Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate that is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site.

Neutrophil-inflicted vasculature damage suppresses immune-mediated optic nerve regeneration.

In adult mammals, injured retinal ganglion cells (RGCs) fail to spontaneously regrow severed axons, resulting in permanent visual deficits. Robust axon growth, however, is observed after intra-ocular injection of particulate β-glucan isolated from yeast. Blood-borne myeloid cells rapidly respond to β-glucan, releasing numerous pro-regenerative factors.

DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses.

Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss.

The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.

Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming.

Identification of in vivo roles of ErbB4-JMa and its direct nuclear signaling using a novel isoform-specific knock out mouse.

Like all receptor tyrosine kinases (RTKs), ErbB4 signals through a canonical signaling involving phosphorylation cascades. However, ErbB4 can also signal through a non-canonical mechanism whereby the intracellular domain is released into the cytoplasm by regulated intramembrane proteolysis (RIP) and translocates to the nucleus where it regulates transcription. These different signaling mechanisms depend on the generation of alternative spliced isoforms, a RIP cleavable ErbB4-JMa and an uncleavable ErbB4-JMb.

Plexins promote Hedgehog signaling through their cytoplasmic GAP activity.

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified neuropilins, established semaphorin receptors, as positive regulators of Hedgehog signaling.

Restoring partial vision to a blind patient.

This paper reports an important breakthrough in partially restoring sight to a man who had lost his vision due to retinitis pigmentosa (RP), a heritable retinal degenerative disease that affects approximately 1 in 4000 people. Long considered an insurmountable challenge, a stellar team of vision scientists, engineers, basic biologists, and others, working together for many years, has enabled a man who had been legally blind for decades to begin distinguishing objects and navigating his environment.

Migrating Pyramidal Neurons Require DSCAM to Bypass the Border of the Developing Cortical Plate.

During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their postmigratory predecessors during the expansion of the upper cortical layers.

Neurobiology: Resetting the axon's batteries.

Neuronal injury can cause mitochondrial damage, leading to reduced energy production, decreased Ca storage capacity, and increased reactive oxygen species. A new study reveals a mechanism to trigger the axonal transport of previously anchored mitochondria and promote neuroprotection and axon regeneration by replacing damaged with functional mitochondria.

THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes.

Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs).

A new neutrophil subset promotes CNS neuron survival and axon regeneration.

Transected axons typically fail to regenerate in the central nervous system (CNS), resulting in chronic neurological disability in individuals with traumatic brain or spinal cord injury, glaucoma and ischemia-reperfusion injury of the eye. Although neuroinflammation is often depicted as detrimental, there is growing evidence that alternatively activated, reparative leukocyte subsets and their products can be deployed to improve neurological outcomes. In the current study, we identify a unique granulocyte subset, with characteristics of an immature neutrophil, that had neuroprotective properties and drove CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors.

RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling.

Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, remain incompletely characterized because most previous efforts relied on measurement of steady-state mRNAs. Here, we use nascent RNA sequencing to profile transcriptional dynamics of primary neuron cultures undergoing network activity shifts.

Greasing the Wheels of Regeneration.

In this issue of Neuron, Yang et al. (2020) identify glycerolipid metabolism as a neuron-intrinsic mechanism that regulates axonal growth and regeneration. Shifting glycerolipid metabolism toward increased triglyceride synthesis blocks PNS neuron regeneration, whereas shifting it toward membrane phospholipid synthesis overcomes regeneration failure in CNS neurons.

Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome.

Objective: SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Na 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug-resistant seizures, developmental delay, and cognitive impairment.

Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition.

Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition.

Protective role of the lipid phosphatase Fig4 in the adult nervous system.

The signaling lipid phosphatidylinositol 3,5-bisphosphate, PI(3,5)P2, functions in vesicular trafficking through the endo-lysosomal compartment. Cellular levels of PI(3,5)P2 are regulated by an enzyme complex comprised of the kinase PIKFYVE, the phosphatase FIG4, and the scaffold protein VAC14. Mutations of human FIG4 cause inherited disorders including Charcot-Marie-Tooth disease type 4J, polymicrogyria with epilepsy, and Yunis-Varón syndrome.

PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors.

Dentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We identify the Plexin family members Plxna2 and Plxna4 as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP) domain and Rap1 small GTPases.

LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair.

Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling molecule broadly expressed by neurons and glia. In adult mice, global inducible () or oligodendrocyte (OL)-lineage specific ablation () of attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), is required for cholesterol homeostasis and differentiation into mature OLs.

Neuropilin-1 promotes Hedgehog signaling through a novel cytoplasmic motif.

Hedgehog (HH) signaling critically regulates embryonic and postnatal development as well as adult tissue homeostasis, and its perturbation can lead to developmental disorders, birth defects, and cancers. Neuropilins (NRPs), which have well-defined roles in Semaphorin and VEGF signaling, positively regulate HH pathway function, although their mechanism of action in HH signaling remains unclear. Here, using luciferase-based reporter assays, we provide evidence that NRP1 regulates HH signaling specifically at the level of GLI transcriptional activator function.

Myelin-Associated Glycoprotein Inhibits Schwann Cell Migration and Induces Their Death.

Remyelination of CNS axons by Schwann cells (SCs) is not efficient, in part due to the poor migration of SCs into the adult CNS. Although it is known that migrating SCs avoid white matter tracts, the molecular mechanisms underlying this exclusion have never been elucidated. We now demonstrate that myelin-associated glycoprotein (MAG), a well known inhibitor of neurite outgrowth, inhibits rat SC migration and induces their death via γ-secretase-dependent regulated intramembrane proteolysis of the p75 neurotrophin receptor (also known as p75 cleavage).

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice.

White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis.