Community Action Needed: Please respond to the NIH RFI
ZFIN ID: ZDB-PUB-120705-14
Spinocerebellar ataxia type 13 mutation associated with disease onset in infancy disrupts axonal pathfinding during neuronal development
Issa, F.A., Mock, A.F., Sagasti, A., and Papazian, D.M.
Date: 2012
Source: Disease models & mechanisms   5(6): 921-929 (Journal)
Registered Authors: Papazian, Diane M., Sagasti, Alvaro
Keywords: none
MeSH Terms:
  • Age of Onset
  • Amino Acid Substitution/genetics
  • Animals
  • Axons/metabolism*
  • Axons/pathology*
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Mice
  • Models, Neurological
  • Motor Neurons/metabolism
  • Motor Neurons/pathology
  • Mutation/genetics*
  • Neurogenesis/genetics*
  • Shaw Potassium Channels/genetics
  • Shaw Potassium Channels/metabolism
  • Spinocerebellar Ataxias/congenital
  • Spinocerebellar Degenerations/genetics*
  • Synapses/pathology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 22736459 Full text @ Dis. Model. Mech.

Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant disease caused by mutations in the Kv3.3 voltage-gated potassium channel. SCA13 exists in two forms, with infant onset characterized by severe cerebellar atrophy, persistent motor deficits, seizures, and intellectual disability, or adult onset characterized by progressive ataxia and cerebellar degeneration. To test the hypothesis that infant- and adult-onset mutations have differential effects on neuronal development that contribute to the age at which SCA13 emerges, we expressed wild type Kv3.3 or infant- or adult-onset mutant proteins in motor neurons in the zebrafish spinal cord. We characterized the development of CaP (caudal primary) motor neurons at ~36 and ~48 hours post-fertilization using confocal microscopy and 3D digital reconstruction. Exogenous expression of wild type Kv3.3 had no significant effect on CaP development. In contrast, CaP neurons expressing the infant-onset mutation made frequent pathfinding errors, sending long, abnormal axon collaterals into muscle territories normally innervated exclusively by RoP (rostral primary) or MiP (middle primary) motor neurons. This phenotype may be directly relevant to infant-onset SCA13 because interaction with inappropriate synaptic targets may trigger cell death during brain development. Importantly, pathfinding errors were not detected in CaP neurons expressing the adult-onset mutation. However, the adult-onset mutation tended to increase the complexity of the distal axonal arbor. From these results, we propose that infant-onset SCA13 is associated with marked changes in the development of Kv3.3-expressing cerebellar neurons that reduce their health and viability early in life, resulting in the withered cerebellum seen in affected children.