Nna1 mediates purkinje cell dendritic development via lysyl oxidase propeptide and NF-κB signaling

Jianxue Li, Xuesong Gu, Yinghua Ma, Monica L. Calicchio, Dong Kong, Yang D. Teng, Lili Yu, Andrew M. Crain, Timothy K. Vartanian, Renata Pasqualini, Wadih Arap, Towia A. Libermann, Evan Y. Snyder, Richard L. Sidman

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 pcdSid 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 pcdSid 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.

Original languageEnglish (US)
Pages (from-to)45-60
Number of pages16
JournalNeuron
Volume68
Issue number1
DOIs
StatePublished - Oct 6 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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