3D Imaging of Axons in Transparent Spinal Cords from Rodents and Nonhuman Primates.

The histological assessment of spinal cord tissue in three dimensions has previously been very time consuming and prone to errors of interpretation. Advances in tissue clearing have significantly improved visualization of fluorescently labelled axons. While recent proof-of-concept studies have been performed with transgenic mice in which axons were prelabeled with GFP, investigating axonal regeneration requires stringent axonal tracing methods as well as the use of animal models in which transgenic axonal labeling is not available.

Fibronectin Matrix Assembly after Spinal Cord Injury.

After spinal cord injury (SCI), a fibrotic scar forms at the injury site that is best characterized by the accumulation of perivascular fibroblasts and deposition of the extracellular matrix protein fibronectin. While fibronectin is a growth-permissive substrate for axons, the fibrotic scar is inhibitory to axon regeneration. The mechanism behind how fibronectin contributes to the inhibitory environment and how the fibronectin matrix is assembled in the fibrotic scar is unknown.

Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury.

Injury to the CNS leads to formation of scar tissue, which is important in sealing the lesion and inhibiting axon regeneration. The fibrotic scar that comprises a dense extracellular matrix is thought to originate from meningeal cells surrounding the CNS. However, using transgenic mice, we demonstrate that perivascular collagen1α1 cells are the main source of the cellular composition of the fibrotic scar after contusive spinal cord injury in which the dura remains intact.

An endophilin-dynamin complex promotes budding of clathrin-coated vesicles during synaptic vesicle recycling.

Clathrin-mediated vesicle recycling in synapses is maintained by a unique set of endocytic proteins and interactions. We show that endophilin localizes in the vesicle pool at rest and in spirals at the necks of clathrin-coated pits (CCPs) during activity in lamprey synapses. Endophilin and dynamin colocalize at the base of the clathrin coat.

Targeted disruption of the Mast syndrome gene SPG21 in mice impairs hind limb function and alters axon branching in cultured cortical neurons.

Mast syndrome (SPG21) is a childhood-onset, autosomal recessive, complicated form of hereditary spastic paraplegia (HSP) characterized by dementia, thin corpus callosum, white matter abnormalities, and cerebellar and extrapyramidal signs in addition to spastic paraparesis. A nucleotide insertion resulting in premature truncation of the SPG21 gene product maspardin underlies this disorder, likely leading to loss of protein function. In this study, we generated SPG21-/- knockout mice by homologous recombination as a possible animal model for SPG21.

Atlastin GTPases are required for Golgi apparatus and ER morphogenesis.

The hereditary spastic paraplegias (SPG1-33) comprise a cluster of inherited neurological disorders characterized principally by lower extremity spasticity and weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Mutations in the gene encoding the large oligomeric GTPase atlastin-1 are responsible for SPG3A, a common autosomal dominant hereditary spastic paraplegia. Here we describe a family of human GTPases, atlastin-2 and -3 that are closely related to atlastin-1.

SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development.

The hereditary spastic paraplegias (HSPs) (SPG1-29) comprise a group of inherited neurological disorders characterized principally by spastic lower extremity weakness due to a length-dependent, retrograde axonopathy of corticospinal motor neurons. Mutations in the gene encoding the dynamin superfamily member atlastin-1, an oligomeric GTPase highly localized to the Golgi apparatus in the adult brain, are responsible for SPG3A, a common autosomal dominant HSP. A distinguishing feature of SPG3A is its frequent early onset, raising the possibility that developmental abnormalities may be involved in its pathogenesis.

Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias.

The hereditary spastic paraplegias (HSPs) comprise a clinically and genetically diverse group of inherited neurological disorders in which the primary manifestation is progressive spasticity and weakness of the lower limbs. The identification of over 25 genetic loci and 11 gene products for these disorders has yielded new insights into the molecular pathways involved in the pathogenesis of HSPs. In particular, causative mutations in proteins implicated in mitochondrial function, intracellular transport and trafficking, axonal development, and myelination have been identified.