The Role of the E3 Ubiquitin Ligase Cdh1-APC in Axon Growth in the Mammalian Brain

Kannan, Madhuvanthi

dc.contributor.advisor	Stegmüller, Judith Dr.	de
dc.contributor.author	Kannan, Madhuvanthi	de
dc.date.accessioned	2013-01-14T15:06:37Z	de
dc.date.available	2013-02-22T23:50:05Z	de
dc.date.issued	2012-09-14	de
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-000D-EF73-C	de
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-1449
dc.description.abstract	Mit der Ausbildung des Axons beginnt die neuronale Differenzierung. Sowohl extrinsische Faktoren der zellulären Umgebung als auch intrinsische Programme tragen zur erfolgreichen Axonogenese bei. Die E3 Ubiquitin Ligase Cdh1-APC (Anaphase Promoting Complex) ist ein zellintrinsischer Inhibitor des Axonenwachstums im Säugergehirn. In diesem Zusammenhang sorgt Cdh1-APC für den proteasomalen Abbau der Transkriptionsfaktoren SnoN und Id2. Jedoch ist unklar, ob Cdh1-APC mit extrinsischen Signalen kooperiert, um Axonwachstum zu steuern. In dieser Studie zeige ich, dass MAPK (mitogen activated protein kinase), PI3K (phosphatidylinositol-3-kinase) und Rho GTPases, Effektoren extrinsischer trophischer Signale, mit dem Cdh1-APC Signalweg interagieren. Während MAPK und PI3K der Inhibition von Cdh1-APC entgegenwirken, unterstützen die GTPasen RhoA und Cdc42 die Wachstumsinhibition von Cdh1-APC. Mechanistischen Einblick gewährte die Identifizierung der HECT (homologous to E6-AP) E3 Ligase Smurf1 als Substrat von Cdh1-APC. Smurf1 stimuliert Axonenwachstum	de
dc.format.mimetype	application/pdf	de
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	de
dc.title	The Role of the E3 Ubiquitin Ligase Cdh1-APC in Axon Growth in the Mammalian Brain	de
dc.type	doctoralThesis	de
dc.title.translated	Die Rolle der E3 Ubiquitin Ligase Cdh1-APC in Axon Wachstum im Gehirn von Säugetieren	de
dc.contributor.referee	Stegmüller, Judith Dr.	de
dc.date.examination	2012-08-22	de
dc.subject.dnb	500 Naturwissenschaften	de
dc.subject.gok	RA 000-Allgemeine Naturwissenschaften	de
dc.description.abstracteng	Neuronal differentiation begins with initiation of the axon. Both extrinsic factors in the neuronal environment and cell-autonomous players contribute to successful axonal morphogenesis. The E3 ubiquitin ligase, Cdh1-Anaphase Promoting Complex (Cdh1-APC) is implicated in cell-intrinsic inhibition of axonal growth in the mammalian brain. In restricting axon growth, Cdh1-APC targets the transcription factors SnoN and Id2 for proteasomal degradation. However, whether the E3 ligase collaborates with extrinsic signaling in controlling axon growth is unknown. In this study, I show that mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and Rho GTPases, effectors of extrinsic trophic signaling, interface with the Cdh1-APC pathway. While MAPK and PI3K activity antagonize Cdh1 inhibition of axon growth, the small Rho GTPases RhoA and Cdc42 are positive mediators of the pathway. A mechanistic insight into the Cdh1-APC/RhoA relationship identified the homologous to E6-AP (HECT) E3 ligase, smad ubiquitination regulatory factor-1 (Smurf1), a negative regulator of RhoA, as a substrate of Cdh1-APC. Smurf1 promotes axon growth downstream of Cdh1-APC by targeting RhoA to proteasomal degradation. Smurf1 binds to Cdh1-APC in a D-box dependent manner and consequently, a stable Smurf1 D-box mutant overcomes Cdh1 inhibition by degrading RhoA and exhibits a gain-of-function in axon growth both on permissive substrates and on myelin. p250 GTPase activating protein (p250GAP), a RhoA inactivator, also participates in the Cdh1-APC pathway alongside Smurf1. Again a positive regulator of axon growth, p250GAP shares a linear pathway downstream of Cdh1-APC. Taken together, my study places Cdh1-APC at the intersection of intrinsic and extrinsic signaling cascades that controls axon growth. Further, my results reiterate an emerging role for the E3 ligase as a suppressor of axon extension and uncover novel candidates for regenerative therapy.	de
dc.contributor.coReferee	Bucher, Gregor Prof. Dr.	de
dc.contributor.thirdReferee	Schlüter, Oliver Dr. Dr.	de
dc.subject.topic	Biology (incl. Psychology)	de
dc.subject.ger	Cdh1-APC	de
dc.subject.ger	RhoA	de
dc.subject.ger	Smurf1	de
dc.subject.ger	p250GAP	de
dc.subject.ger	Ubiquitination	de
dc.subject.ger	Axonenwachstum	de
dc.subject.ger	Regeneration	de
dc.subject.eng	Cdh1-APC	de
dc.subject.eng	RhoA	de
dc.subject.eng	Smurf1	de
dc.subject.eng	p250GAP	de
dc.subject.eng	ubiquitination	de
dc.subject.eng	axon growth	de
dc.subject.eng	regeneration	de
dc.subject.bk	30.00 Naturwissenschaften allgemein: Allgemeines	de
dc.identifier.urn	urn:nbn:de:gbv:7-webdoc-3690-5	de
dc.identifier.purl	webdoc-3690	de
dc.affiliation.institute	Biologische Fakultät	de
dc.description.embargoed	2013-02-22	de
dc.identifier.ppn	739688340	de

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