Organ lumen morphogenesis in C. elegans

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Internal (visceral) organs are built from tubular structures, and lumenal epithelia carry out their essential function. Tubulogenesis and lumen formation require a specific type of epithelial rearrangement, distinct from the better known process of cell sheet spreading. The downstream molecules and structural dynamics involved in the process of tubulogenesis are not known. We have recently identified the first effector molecule essential for tube and lumen morphogenesis. erm-1, the C. elegans ortholog of the ezrin-radixinmoesin family of cytoskeleton-membrane linkers, is required for the morphogenesis of the intestine, excretory canals and tubular gonad, revealing that distinct lumenal epithelia share common scaffolding elements. Here, a screen is proposed to isolate tubulogenesis genes by examining their loss-of-function phenotypes, in order to recover molecules of in vivo relevance for this process. Transgenic lines expressing fluorescently labeled apical (ERM-1::GFP) versus basolateral (NFM-1 ::GFP) epithelial membrane markers of the three tubular organs will be screened by genome-wide RNA interference (RNAi) for morphological defects of the lumena (ERM-I::GFP) and shapes (NFM-1::GFP) of these epithelia. Every transcript predicted form the completed C. elegans genome sequence will be specifically and independently targeted. The screen is devised to identify genes involved in the structural process of epithelial rearrangement required for tubulogenesis, bypassing upstream regulators of organ morphogenesis. The use of subcellular markers localized to distinct apical and basolateral membrane domains should also identify molecules involved in generating apico-basal polarity, a process fundamental to tubular epithelia. This project seeks to understand a fundamental biological phenomenon crucial to the development of all higher organisms by using a simple model organism and taking advantage of available high-throughput resources.