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alternative splicing, phosphorylation, retinal development, Disabled-1, Reelin

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 and 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.





Autor: Gao, Zhihua

Fuente: https://era.library.ualberta.ca/


Introducción



University of Alberta Modulation of Disabled-1 Activity by Alternative Splicing by Zhihua Gao A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Oncology Department of Oncology ©Zhihua Gao Spring 2011 Edmonton, Alberta 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 authors prior written permission. Examining Committee Dr.
Roseline Godbout, Department of Oncology Dr.
Hanne Ostergaard, Department of Medical Microbiology & Immunology Dr.
Andrew Shaw, Department of Oncology Dr.
James Stone, Department of Biochemistry Dr.
Ruth Slack, University of Ottawa, Canada Dedication This thesis is dedicated to my parents, Gangsheng Gao (1940-1995) and Maiqiu Zhou for their unconditional love and lifetime support. 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...





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