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NOTCH4 Is an Inhibitor of Canonical Notch Signalling

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NOTCH4 Is an Inhibitor of Canonical Notch Signalling NOTCH4 is an inhibitor of canonical Notch signalling Alexander James B.Sc. (hons) A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy. St Vincent’s Clinical School Faculty of Medicine Victor Chang Cardiac Research Institute December 2012 i | Page THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: James First name: Alexander Other name/s: Campbell Abbreviation for degree as given in the University calendar: PhD School: St Vincent’s Clinical School Faculty: Medicine Title: Notch4 is an inhibitor of canonical Notch signalling. Abstract 350 words maximum: (PLEASE TYPE) Notch signal transduction is evolutionarily conserved with essential functions identified in numerous species from C.elegans to H.Sapiens. Notch is critical during embryonic development, in the adult, and in cancer. In mammals there are four Notch receptors; much of our understanding of Notch signalling comes from the study of NOTCH1. During embryogenesis, Notch1 is widely expressed and is required in numerous processes including blood vessel formation and remodelling (angiogenesis). The view of Notch signal transduction, achieved primarily through studying NOTCH1, is that Notch receptors undergo processing and are transported to the cell surface as a heterodimer. Ligand binding triggers a series of proteolytic cleavages leading to the release of the Notch intracellular domain, which translocates to the nucleus to activate transcription. In contrast to NOTCH1, little is known about NOTCH4; Notch4 is expressed in endothelial cells of the circulatory system, trans-activation by ligand is difficult to detect, and a phenotype in mice, reported to be null for Notch4 (Notch4d1 allele), has not been identified. Here, further analysis of NOTCH4 has revealed many features that are in contrast to NOTCH1: (i) unprocessed NOTCH4 was present on the cell surface, (ii) ligand did not trans-activate NOTCH4 signalling, (iii) NOTCH4 inhibited NOTCH1 signal transduction in a dose dependent manner, (iv) NOTCH4 induced the differentiation of myoblasts, and (v) subcellular localisation of NOTCH4 was different to NOTCH1, and coexpression resulted in NOTCH1 adopting the NOTCH4 pattern of localisation. In addition, postnatal retinal angiogenesis was examined in mice carrying the Notch4d1 allele. A delay in the expansion of the retinal vasculature was equally observed in both Notch4d1+/- and Notch4d1-/- mice. This suggested that Notch4d1 was not a null allele. Fittingly, the Notch4d1 allele produced transcripts that encode for much of the extracellular domain of NOTCH4. The expression pattern of this transcript was equivalent to Notch4 in mouse embryos. Like full length NOTCH4, expression of a cDNA based on this transcript also inhibited NOTCH1 signal transduction. These studies reveal for the first time a function for NOTCH4 that is, as an inhibitor of NOTCH1. Accordingly it is postulated that Notch4 will have a crucial function in angiogenesis, since Notch1 is required for angiogenesis and Notch4 is expressed in endothelial cells of the circulatory system. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). ………………………………………………… ……………………………………..……………… ……….……………………...…….… ………… Witness Date Signature The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ii | Page Abstract Notch signal transduction is evolutionarily conserved with essential functions identified in numerous species from C.elegans to H.Sapiens. Notch is critical during embryonic development, in the adult, and in cancer. In mammals there are four Notch receptors; much of our understanding of Notch signalling comes from the study of NOTCH1. During embryogenesis, Notch1 is widely expressed and is required in numerous processes including blood vessel formation and remodelling (angiogenesis). The view of Notch signal transduction, achieved primarily through studying NOTCH1, is that Notch receptors undergo processing and are transported to the cell surface as a heterodimer. Ligand binding triggers a series of proteolytic cleavages leading to the release of the Notch intracellular domain, which translocates to the nucleus to activate transcription. In contrast to NOTCH1, little is known about NOTCH4; Notch4 is expressed in endothelial cells of the circulatory system, trans-activation by ligand is difficult to detect, and a phenotype in mice, reported to be null for Notch4 (Notch4d1 allele), has not been identified. Here, further analysis of NOTCH4 has revealed many features that are in contrast to NOTCH1: (i) unprocessed NOTCH4 was present on the cell surface, (ii) ligand did not trans-activate NOTCH4 signalling, (iii) NOTCH4 inhibited NOTCH1 signal transduction in a dose dependent manner, (iv) NOTCH4 induced the differentiation of myoblasts, and (v) subcellular localisation of NOTCH4 was different to NOTCH1, and coexpression resulted in NOTCH1 adopting the NOTCH4 pattern of localisation. In addition, postnatal retinal angiogenesis was examined in mice carrying the Notch4d1 allele. A delay in the expansion of the retinal vasculature was equally observed in both Notch4d1+/- and Notch4d1-/- mice. This suggested that Notch4d1 was not a null allele. Fittingly, the Notch4d1 allele produced transcripts that encode for much of the extracellular domain of NOTCH4. The expression pattern of this transcript was equivalent to Notch4 in mouse embryos. Like full length NOTCH4, expression of a cDNA based on this transcript also inhibited NOTCH1 signal transduction. These studies reveal for the first time a function for NOTCH4 that is, as an inhibitor of NOTCH1. Accordingly it is postulated that Notch4 will have a crucial function in angiogenesis, since Notch1 is required for angiogenesis and Notch4 is expressed in endothelial cells of the circulatory system. iii | Page Originality statement ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. iv | Page Copyright statement ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Authenticity statement ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed …………………………………………….............. Date …………………………………………….............. v | Page Acknowledgments I would like to thank both my supervisor Professor Sally Dunwoodie and co-supervisor Dr Gavin Chapman for all their help and support throughout my PhD. Their approachability, advice and knowledge were invaluable during the course of these studies. I would also like to thank all the present and past members of the Dunwoodie laboratory whose help made this work possible. There have been too many people to thank individually among the staff and students of the Victor Chang Cardiac Research Institute who have provided advice and
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