Erben, Larissa: Expression and Function of ErbB4 Splice Variants in the Central Nervous System. - Bonn, 2019. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc:
author = {{Larissa Erben}},
title = {Expression and Function of ErbB4 Splice Variants in the Central Nervous System},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2019,
month = jul,

note = {Neuregulins and their cognate neuronal receptor tyrosine kinase ErbB4 (avian erythroblastosis virus oncogene B4) are genetically linked with an increased risk for schizophrenia. NRG/ErbB4 signaling regulates neurodevelopment, synaptic plasticity, network activity and modulates several neurotransmitter systems. Four ErbB4 isoforms are generated by alternative splicing in the juxtamembrane (JMa and JMb) and cytoplasmic region (Cyt-1 and Cyt-2). These isoforms mediate unique downstream signaling pathways exerting divergent biological functions. Although the expression of ErbB4 variants is altered in postmortem brains of schizophrenia patients, little is known about the distribution and functions of ErbB4 isoforms in the brain. This dissertation investigates the hypothesis that ErbB4 variants are differentially expressed in the central nervous system and uniquely contribute to ErbB4’s role in the brain. Using next-generation sequencing, major and rare ErbB4 variants in the mouse brain are first identified. Then, to analyze splice variants at the cellular level, a novel ultrasensitive exon-specific in situ hybridization approach is implemented and validated, and quantitation tools developed. I extensively describe the mRNA distribution of the four major ErbB4 variants in the mouse brain, identify spatiotemporal- and cell type-specific expression, and expand these findings to the human brain. The examination of subcellular distribution of ErbB4 protein in distinct neuronal cell types reveals that in contrast to the somatodendritic restriction of ErbB4 in cultured gamma-aminobutyric acid (GABA)ergic interneurons, ErbB4 is present on axonal projections of dopaminergic neurons, independent of the isoform. Finally, we generated isoform-specific Cyt-1 mutant mice to explore in vivo functions of this ErbB4 variant. Although Cyt-1 variants comprise 40% of all ErbB4 transcripts in the brain, extensive molecular, transcriptomic, neurodevelopmental, neurochemical and behavioral evaluation show modest phenotypic effects, suggesting a possible compensation throughout development or redundant functions of Cyt isoforms. These findings advance our understanding of the basic biology of ErbB4 isoforms and their pathophysiological changes in schizophrenia.},
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