TheC. elegansperoxidasin PXN-2 is essential for embryonic morphogenesis and inhibits adult axon regeneration

Abstract

SUMMARYPeroxidasins form a highly conserved family of extracellular peroxidases of unknown cellular function. We identified the C. elegans peroxidasin PXN-2 in screens for mutants defective in embryonic morphogenesis. We find that PXN-2 is essential for specific stages of embryonic morphogenesis and muscle-epidermal attachment, and is also required postembryonically for basement membrane integrity. The peroxidase catalytic activity of PXN-2 is necessary for these developmental roles. pxn-2 mutants display aberrant ultrastructure of the extracellular matrix, suggesting a role in basement membrane consolidation. PXN-2 affects specific axon guidance choice points in the developing nervous system but is dispensable for maintenance of process positions. In adults, loss of pxn-2 function promotes regrowth of axons after injury, providing the first evidence that C. elegans extracellular matrix can play an inhibitory role in axon regeneration. Loss of function in the closely related C. elegans peroxidasin pxn-1 does not cause overt developmental defects. Unexpectedly, pxn-2 mutant phenotypes are suppressed by loss of function in pxn-1 and exacerbated by overexpression of wild-type pxn-1, indicating that PXN-1 and PXN-2 have antagonistic functions. These results demonstrate that peroxidasins play crucial roles in development and reveal a new role for peroxidasins as extracellular inhibitors of axonal regeneration.

An active role for basement membrane assembly and modification in tissue sculpting

“…Type IV collagen has the unique ability to form intermolecular covalent bonds, which is thought to endow the basement membrane with its ability to withstand mechanical stress (Khoshnoodi et al, 2008;Vanacore et al, 2009). Consistent with this notion, loss of the enzyme peroxidasin, which localizes to basement membranes and catalyzes a conserved intermolecular sulfilimine bond between type IV collagen molecules, reduces tissue integrity in Drosophila, Caenorhabditis elegans and zebrafish (Bhave et al, 2012;Fidler et al, 2014;Gotenstein et al, 2010). The biochemical interactions linking the initial laminin meshwork to the cross-linked collagen lattice are unclear.…”

Proprotein Convertase Processing Enhances Peroxidasin Activity to Reinforce Collagen IV

“…The enzyme peroxidasin (Pxdn), a basement membrane-associated heme peroxidase, catalyzes the formation of sulfilimine crosslinks, a process critical for BM and tissue integrity (4). For example, peroxidasin loss of function in Drosophila and Caenorhabditis elegans compromises gut architecture and leads to early lethality (4,5). In addition to structural reinforcement, the sulfilimine cross-link also confers immune privilege to the collagen IV auto-antigen in human Goodpasture's disease, a devastating condition presenting as rapidly progressive glomerulonephritis with or without pulmonary hemorrhage.…”

Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways

“…Subsequent studies by several laboratories have described the similar features of axon regeneration in C. elegans compared with mammals, and provided some insights into the genetic basis of axon regeneration (16)(17)(18)(19)(20)(21). The development of microfluidic chambers to automate the immobilization of worms, combined with laser axotomy, raises the hope for high throughput axon regeneration screening assays (22)(23)(24)(25).…”