Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding

TLDR

Spinal muscular atrophy is an autosomal recessive disorder marked by loss of α‑motoneurons caused by reduced survival motor neuron protein levels. The study aimed to model SMA in zebrafish to investigate how diminished Smn levels affect motoneuron development. Researchers knocked down Smn in zebrafish embryos using antisense morpholinos, creating an SMA model. Smn depletion produced motor axon pathfinding defects that are cell autonomous, revealing Smn’s role in axon development and implying that early defects may lead to later motoneuron loss.

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of α motoneurons in the spinal cord. SMA is caused by low levels of the ubiquitously expressed survival motor neuron (Smn) protein. As it is unclear how low levels of Smn specifically affect motoneurons, we have modeled SMA in zebrafish, a vertebrate model organism with well-characterized motoneuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, we found motor axon–specific pathfinding defects. Reduction of Smn in individual motoneurons revealed that smn is acting cell autonomously. These results show for the first time, in vivo, that Smn functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss.