Abstract
The molecular pathways controlling cerebellar Purkinje cell dendrite formation and maturation are poorly understood. The
Purkinje cell degeneration (
pcd) mutant mouse is characterized by mutations in
Nna1, a gene discovered in an axonal regenerative context, but whose actual function in development and disease is unknown. We found abnormal development of Purkinje cell dendrites in postnatal
pcd
Sid
mice and linked this deficit to a deletion mutation in exon 7 of
Nna1. With single cell gene profiling and virus-based gene transfer, we analyzed a molecular pathway downstream to
Nna1 underlying abnormal Purkinje cell dendritogenesis in
pcd
Sid
mice. We discovered that mutant
Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-κB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into
Nna1's role in neuronal development and why its absence renders Purkinje cells more vulnerable.
► The pcdSid mutant mouse features a deletion of Nna1 exon 7 that affects postnatal PCs ► Molecules downstream from mutant Nna1 mediate underdevelopment of pcdSid PC dendrites ► Increased transfer of Lox propeptide into pcdSid PC nucleus reduces NF-κB RelA levels ► Reduced NF-κB signaling suppresses PC dendrite development via altered MAP1B and MAP2