Lecture on September 24, 2015
Time: 10:00, Sept. 24, 2015
Venue: Room 506, Museum for Aquatic Organisms
Speaker: Prof. Christroph Winkler
Department of Biological Sciences, National University of Singapore, Singapore
Title: Transcriptome analysis of FACS-sorted motor neurons and Schwann cells reveals pre-mRNA splicing defects in a zebrafish model for Spinal Muscular Atrophy
Introduction to the Lecture:
Spinal muscular atrophy (SMA) is a progressive human neurodegenerative disease that leads to degeneration of lower motoneurons and paralysis. With an incidence of 1 in 6000 live births, it represents the most frequent genetic cause of infant death in humans. SMA is caused by reduced levels of the Survial Motoneuron (SMN) protein, which is implicated in snRNP assembly and thus affects pre-mRNA splicing. How mutations in the ubiquitously expressed SMN gene result in motoneuron degeneration remains unclear. We used transcriptome analysis in a zebrafish model for SMA to identify mRNAs that are aberrantly spliced under SMN-deficient conditions. This lead to the identification of neurexin2a (nrxn2a), which is essential for normal motoneuron function and affected in both zebrafish and mouse models for SMA. In our zebrafish SMA model, we also observed deficiencies in Schwann cells in a manner independent of motoneuron activity. Strikingly, we found that transgenic expression of SMN exclusively in Schwann cells could rescue motoneuron defects in the zebrafish SMA model. This strongly suggests that non-cell autonomous defects contribute to motoneuron impairments in SMN deficient zebrafish. To gain insight into the underlying mechanism, we purified Schwann cells from SMA zebrafish by fluorescence activated cell sorting (FACS). RNA deep sequencing was performed to identify aberrantly spliced transcripts that impact the interaction between Schwann cells and motoneurons during motor synapse formation and maintenance.