ANALYZING NEURAL CIRCUIT FUNCTION AND DEFICIENCIES IN A ZEBRAFISH MODEL FOR SPINAL MUSCULAR ATROPHY

Abstract

Spinal muscular atrophy (SMA) is caused by reduced levels of the ubiquitously expressed survival motor neuron (Smn), which leads to motor neuron degeneration and muscle atrophy. Here I report that reduction of Smn in zebrafish, leads to a marked reduction in neural stem cell/progenitor marker expression which was associated with defects in neuron organization, proneural gene expression and ventral neuron markers. While motor neuron formation was not affected during Smn deficient conditions, defects in ventral interneuron formation was observed together with abnormalities in motor axon morphology. I found that Notch inhibition resulted in increased proneural expression and interneuron formation which coincided with rescue of the motor axon phenotype. Furthermore, knock-in of egfp and mcherry-smn into loci relevant for interneuron differentiation was attempted, to study their development and relevance in SMA. Lastly, Dmrt3 function was studied in the context of ventral interneuron progenitor formation using crispants and mutants generated with CRISPR/Cas9.