Neurogenesis, Neuron Resilience, and Neurodegeneration in a Zebrafish Model of Human Disease

Christoph Winkler

The zebrafish, Danio rerio, has emerged as a powerful model in neurobiology and for investigating human neurodegenerative diseases. During early embryonic development, formation of the nervous system depends on the transition from symmetric progenitor cell divisions to asymmetric divisions that drive neuronal differentiation. This process involves spatial redistribution of fate determinants, although the underlying mechanisms remain unclear. We have shown that the protein tyrosine phosphatase receptor Ptprz1b, earlier reported to promote stemness in human glioma cells, maintains symmetric divisions to expand progenitor pools in the zebrafish nervous system. We demonstrate that the depletion of maternal Ptprz1b pools results in redistribution of fate determinants and thereby controls the timing of neurogenesis onset.

In a second project, we used HDR-mediated knock-in to generate a zebrafish model for spinal muscular atrophy (SMA), a common motor neuron degeneration disorder caused by low levels of ubiquitously expressed Survival Motor Neuron (Smn) protein. Smn is essential for snRNP assembly and pre-mRNA splicing, yet the basis of selective motor neuron vulnerability remains poorly understood. Using in vivo imaging in zebrafish embryos, we identified early axonal transport defects in affected motor neurons, long before SMA pathological hallmarks become evident. Transcriptome profiling of motor neurons revealed splicing defects in transcripts critical for axonal transport. Notably, a subset of mutant MNs persisted into late symptomatic stages, and transcriptome analysis uncovered several upregulated candidate genes that conferred enhanced resilience to Smn deficiency. Together, our findings underscore the value of the zebrafish model for elucidating disease mechanisms and identifying potential therapeutic targets.