LAUSR

Zamolodchikov et al. A short isoform of coagulation factor XII mRNA is expressed by neurons in the human brain. Neuroscience 2019; 413:294‐307. Factor XII is reported in brains of Alzheimer's disease and multiple sclerosis patients, but how it gets in the brain and what it does there are puzzling. Zamolodchikov and colleagues now report finding a splice variant of factor XII mRNA expressed by certain neurons in brains of humans—but not mice. When translated, this splice variant yields a short form of factor XII consisting of a highly truncated heavy chain (essentially, just the proline‐rich domain) plus the complete catalytic domain. Recombinant short factor XII (FXII297–596) is activated by plasma kallikrein and can reciprocally activate plasma prekallikrein. Interestingly, FXII297–596 functions much like cathepsin K‐cleaved factor XIIa, which readily activates pro‐hepatocyte growth fac‐ tor (pro‐HGF) to HGF by limited proteolysis. (The canonical ac‐ tivator of HGF, termed HGFA, is evolutionarily related to factor XII.) HGF signals via its receptor, c‐Met, which is thought to be important in neuronal development and survival. On the other hand, dysregulation of HGF/c‐Met signaling is implicated in neu‐ rodevelopmental disorders and neurodegeneration. This novel splice variant of factor XII may therefore be a player in an im‐ portant signaling axis in the CNS.