title: Polarizing the Neuron through Sustained Co-expression of Alternatively Spliced Isoforms.
abstract: Alternative splicing (AS) is an important source of proteome diversity in eukaryotes. However, how this affects protein repertoires at a single-cell level remains an open question. Here, we show that many 3'-terminal exons are persistently co-expressed with their alternatives in mammalian neurons. In an important example of this scenario, cell polarity gene Cdc42, a combination of polypyrimidine tract-binding, protein-dependent, and constitutive splicing mechanisms ensures a halfway switch from the general (E7) to the neuron-specific (E6) alternative 3'-terminal exon during neuronal differentiation. Perturbing the nearly equimolar E6/E7 ratio in neurons results in defects in both axonal and dendritic compartments and suggests that Cdc42E7 is involved in axonogenesis, whereas Cdc42E6 is required for normal development of dendritic spines. Thus, co-expression of a precise blend of functionally distinct splice isoforms rather than a complete switch from one isoform to another underlies proper structural and functional polarization of neurons.
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Yap
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke NUS Graduate Medical School, 8 College Road, 169857 Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Friedman
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke NUS Graduate Medical School, 8 College Road, 169857 Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore, Singapore.
authors.forename: H Shawn
authors.initials: HS
authors.lastname: Je
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK; School of Biological Sciences, Nanyang Technological University, 637551 Singapore, Singapore. Electronic address: eugene.makeyev@kcl.ac.uk.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Makeyev
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D005091:Exons / Q000235:genetics; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D022821:RNA Splice Sites; D020764:cdc42 GTP-Binding Protein