Dokument: Genetische Identifizierung von Regulatoren der Epithelentwicklung im Nematoden Caenorhabditis elegans

Titel:	Genetische Identifizierung von Regulatoren der Epithelentwicklung im Nematoden Caenorhabditis elegans
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=13959
URN (NBN):	urn:nbn:de:hbz:061-20100202-133619-6
Kollektion:	Dissertationen
Sprache:	Deutsch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Pilipiuk, Jennifer [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 8,47 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 29.01.2010 / geändert 29.01.2010
Beitragende:	PD Dr. Bossinger, Olaf [Gutachter] Prof. Dr. Beye, Martin [Gutachter]
Stichwörter:	Zellpolarität, Epithelien, Zell-Kontaktstruktur, Spermatheka, IP3, Ca2+, Ovulation, Caenorhabditis elegans
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibungen:	Eine herausragende Eigenschaft von Epithelien ist die Ausbildung interzellulärer Kontaktstrukturen entlang der lateralen Membrandomäne der Epithelzellen. Im Nematoden Caenorhabditis elegans rekrutiert das LET-413 Protein den DLG-1–AJM-1 Komplex (DAC). Dieser ist letztendlich für die Ausbildung der elektronendichten Struktur der sog. „C. elegans apical junction“ verantwortlich. Diese formt einen kontinuierlichen Adhäsions-Gürtel um den Apex aller embryonalen Epithelzellen. Im Rahmen dieser Arbeit wurde nun zunächst die Rolle des LET-413 Proteins und des DAC während der Postembryogenese von C. elegans und dabei besonders bei der Ausbildung des Spermatheka-Epithels analysiert. Dabei zeigte sich, dass die durch RNAi (RNA-vermittelte Interferenz) induzierte Herunterregulierung von LET-413 und des DAC offensichtlich nicht die Funktionen bereits während der Embryonalentwicklung etablierter Epithelien beeinträchtigt. Im Gegensatz dazu wird die Ausbildung „neuer Epithelien“ während der Postembryogenese massiv gestört und führt im Falle der Spermatheka zu einer fast kompletten Sterilität. Der DAC wird wie im Embryo, so auch in der Spermatheka durch LET-413 rekrutiert, was auf eine grundsätzliche Konservierung des Mechanismus der Ausbildung interzellulärer Kontaktstrukturen während der Embryogenese und der Postembryogenese hindeutet. Die molekularen Details dieses Mechanismus sind aber weitestgehend unbekannt. In dieser Doktorarbeit gelang es nun erstmalig die durch let-413 und dlg-1 RNAi induzierten Phänotypen, Sterilität und embryonale Letalität, durch Mutationen in anderen Genen zu supprimieren. Im Falle des ipp-5 und des itr-1 Gens handelt es sich dabei um eine Funktionsverlust-Mutation in einer Inositol Polyphosphat 5-Phosphatase beziehungsweise eine Funktionszugewinn-Mutation im Inositol Triphosphat(IP3) Rezeptor. Dies deutet auf eine wichtige Funktion des IP3/Ca2+ Signals bei der Rettung der let-413 und dlg-1 Phänotypen hin. Nach EMS-Mutagenese konnten dann in einem klassischen F2-Screen weitere Suppressor-Mutanten identifiziert werden, die den let-413(RNAi) Phänotyp unterdrücken. Die in dieser Arbeit vorgelegten Ergebnisse legen somit den Grundstein für einen neuen Ansatz, dessen Ziel es ist mit Hilfe weiterer Suppressor-Analysen den molekularen Wirkmechanismus der let-413 und dlg-1 Genfunktion endgültig aufzuklären. A hallmark of epithelial differentiation is the formation of highly elaborate cell-cell junctions along the lateral membrane domain of epithelial cells. In the nematode Caenorhabditis elegans, the LET-413 protein recruits the DLG-1–AJM-1 complex (DAC), which organizes the electron-dense structure of the so-called “C. elegans apical junction” and finally forms a circumferential junctional belt around the epithelial apex. In this thesis, the let-413 and dlg-1 gene functions were analysed by RNAi (RNA-mediated interference) during postembryonic development of C. elegans, mainly focusing on the spermatheca, a simple organ that receives and stores sperms. RNAi against let-413 and dlg-1 seems not to disrupt functions of epithelia that have been already formed during embryogenesis (e.g. the pharynx, the intestine or the hypodermis). However, the establishment of the spermatheca epithelium is severely disturbed, which in the end causes sterility in C. elegans. The recruitment of the DAC by the LET-413 protein suggests a common underlying but so far unknown mechanism that is conserved in postembryonic and embryonic development of C. elegans. This thesis for the first time demonstrates rescue of both embryonic and postembryonic let-413 and dlg-1 RNAi-induced phenotypes by a loss-of-function mutation in ipp-5 and a gain-of-function mutation in itr-1 encoding for a type I 5-phosphatase and the inositol 1,4,5(IP3)-triphosphate receptor, respectively. These results suggest that IP3/Ca2+ signals somehow trigger a so far unknown rescue pathway that nevertheless requires a minimal amount of LET-413 protein function. To further elucidate this pathway, a classical F2 EMS mutagenesis pilot screen identified 4 putative suppressors (dus8-dus11) of the let-413(RNAi) phenotype in the spermatheca. In addition, dus8-dus11 also suppress embryonic let-413 and dlg-1 RNAi phenotypes, further supporting the idea of a common basic mechanism operating during epithelial development in the embryo and during postembryogenesis.
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Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Genetik
Dokument erstellt am:	02.02.2010
Dateien geändert am:	29.01.2010
Promotionsantrag am:	01.12.2009
Datum der Promotion:	25.01.2010