No obvious abnormality in mice deficient in receptor protein tyrosine phosphatase beta.

The development of neurons and glia is governed by a multitude of extracellular signals that control protein tyrosine phosphorylation, a process regulated by the action of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Receptor PTPbeta (RPTPbeta; also known as PTPzeta) is expressed predominantly in the nervous system and exhibits structural features common to cell adhesion proteins, suggesting that this phosphatase participates in cell-cell communication. It has been proposed that the three isoforms of RPTPbeta play a role in regulation of neuronal migration, neurite outgrowth, and gliogenesis. To investigate the biological functions of this PTP, we have generated mice deficient in RPTPbeta. RPTPbeta-deficient mice are viable, are fertile, and showed no gross anatomical alterations in the nervous system or other organs. In contrast to results of in vitro experiments, our study demonstrates that RPTPbeta is not essential for neurite outgrowth and node formation in mice. The ultrastructure of nerves of the central nervous system in RPTPbeta-deficient mice suggests a fragility of myelin. However, conduction velocity was not altered in RPTPbeta-deficient mice. The normal development of neurons and glia in RPTPbeta-deficient mice demonstrates that RPTPbeta function is not necessary for these processes in vivo or that loss of RPTPbeta can be compensated for by other PTPs expressed in the nervous system.

Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels.

Rapid conduction in myelinated axons depends on the generation of specialized subcellular domains to which different sets of ion channels are localized. Here, we describe the identification of Caspr2, a mammalian homolog of Drosophila Neurexin IV (Nrx-IV), and show that this neurexin-like protein and the closely related molecule Caspr/Paranodin demarcate distinct subdomains in myelinated axons. While contactin-associated protein (Caspr) is present at the paranodal junctions, Caspr2 is precisely colocalized with Shaker-like K+ channels in the juxtaparanodal region. We further show that Caspr2 specifically associates with Kv1.1, Kv1.2, and their Kvbeta2 subunit. This association involves the C-terminal sequence of Caspr2, which contains a putative PDZ binding site. These results suggest a role for Caspr family members in the local differentiation of the axon into distinct functional subdomains.

Nerve conduction block by nitric oxide that is mediated by the axonal environment.

Conduction in rat peripheral nerve has been monitored following the stimulated release of nitric oxide (NO) from diethylamine-NONOate (DEA-NONOate). Branches of the sciatic nerve were dissected, but left otherwise intact, and propagating signals recorded externally. At levels consistent with inflammation, NO exposure resulted in a complete loss of the compound action potential. Conduction was fully restored on removal of the drug. Most notably, this loss of excitability was dependent on the axonal environment. Removal of the connective tissue sheaths surrounding the nerve bundle, a process that normally enhances drug action, prevented block of signal propagation by nitric oxide. The epineurium seemed not to be required, and the decreased susceptibility to NO appeared to be correlated with a gradual loss of a component of the endoneurium that surrounds individual fibers. Tested on the rat vagus nerve, NO eliminated action potentials in both myelinated and unmyelinated fibers. One chemical mechanism that is consistent with the reversibility of block and the observed lack of effect of 8-Br-cGMP on conduction is the formation of a nitrosothiol through reaction of NO with a sulfhydryl group. In contrast to DEA-NONOate, S-nitrosocysteine, which can both transfer nitrosonium cation (NO+) to another thiol and also release nitric oxide, was effective on both intact and desheathed preparations. It has previously been demonstrated that chemical modification of invertebrate axons by sulfhydryl-reactive compounds induces a slow inactivation of Na+ channels. Nitric oxide block of axonal conduction may contribute to clinical deficits in inflammatory diseases of the nervous system.