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Permanent link (DOI): https://doi.org/10.7939/R3DH14

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Modulation of Disabled-1 Activity by Alternative Splicing Open Access

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Other title
Subject/Keyword
alternative splicing
phosphorylation
retinal development
Disabled-1
Reelin
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Gao, Zhihua
Supervisor and department
Godbout, Roseline (Oncology)
Examining committee member and department
Slack, Ruth (University of Ottawa)
Shaw, Andrew (Oncology)
Stone, James (Biochemistry)
Ostergaard, Hanne (Medical Microbiology & Immunology)
Department
Department of Oncology
Specialization
Experimental Oncology
Date accepted
2012-06-08T09:23:15Z
Graduation date
2011-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The Reelin-Disabled-1 (Dab1) signaling pathway plays a key role in regulating neuronal positioning and synaptic plasticity. Binding of Reelin to its receptors induces tyrosine phosphorylation of the intracellular adaptor protein Dab1. Tyrosine-phosphorylated Dab1 not only rapidly transmits the Reelin signal to downstream effectors but also terminates Reelin-mediated signaling by targeting itself for degradation. Multiple alternatively-spliced Dab1 isoforms have been reported; however, the functions of Dab1 isoforms, other than the commonly studied Dab1 form, remain unknown. Here, we show that an alternatively-spliced chicken Dab1 isoform, chDab1-E, is missing two critical tyrosine sites implicated in Reelin signaling, and is not tyrosine phosphorylated upon Reelin stimulation. Knockdown of Dab1-E in chick retina results in a significant reduction in the number of proliferating cells and promotes ganglion cell differentiation, suggesting that chDab1-E is involved in the maintenance of the retinal progenitor pool and retinogenesis. Furthermore, we show that chDab1-E is serine/threonine phosphorylated by cyclin-dependent kinase 2 (Cdk2) independent of Reelin. ChDab1-E phosphorylation destabilizes the protein through proteasome degradation, indicating that Dab1 turnover can be regulated by both Reelin-independent serine/threonine phosphorylation and Reelin-dependent tyrosine phosphorylation. Finally, we demonstrate that Dab1 alternative splicing is highly complex in mouse, with the potential of generating 16 isoforms that differ primarily in the tyrosine-rich region of Dab1. We have identified 11 murine Dab1 isoforms that are differentially phosphorylated on tyrosine residues, suggesting that different Dab1 isoforms may differentially respond to Reelin stimulation. We propose that Dab1 alternative splicing provides an exquisitely-regulated mechanism to fine-tune the activity of Reelin signaling in a temporal and spatial manner, allowing cells that express different Dab1 isoforms to differentially respond to the Reelin signal during development. Our studies support diverse roles for alternatively-spliced Dab1 isoforms during central nervous system development. We propose a model whereby Dab1 alternative splicing tightly regulates neurogenesis, neuronal migration and synaptic plasticity through both Reelin-independent and Reelin-dependent signaling events. Our findings provide new insight into the roles of developmentally-regulated alternative splicing in controlling gene function and coordinating complex processes at different developmental stages.
Language
English
DOI
doi:10.7939/R3DH14
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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