Notch and Ras promote sequential steps of excretory tube development in C. elegans

Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Development (Impact Factor: 6.46). 08/2011; 138(16):3545-55. DOI: 10.1242/dev.068148
Source: PubMed


Receptor tyrosine kinases and Notch are crucial for tube formation and branching morphogenesis in many systems, but the specific cellular processes that require signaling are poorly understood. Here we describe sequential roles for Notch and Epidermal growth factor (EGF)-Ras-ERK signaling in the development of epithelial tube cells in the C. elegans excretory (renal-like) organ. This simple organ consists of three tandemly connected unicellular tubes: the excretory canal cell, duct and G1 pore. lin-12 and glp-1/Notch are required to generate the canal cell, which is a source of LIN-3/EGF ligand and physically attaches to the duct during de novo epithelialization and tubulogenesis. Canal cell asymmetry and let-60/Ras signaling influence which of two equivalent precursors will attach to the canal cell. Ras then specifies duct identity, inducing auto-fusion and a permanent epithelial character; the remaining precursor becomes the G1 pore, which eventually loses epithelial character and withdraws from the organ to become a neuroblast. Ras continues to promote subsequent aspects of duct morphogenesis and differentiation, and acts primarily through Raf-ERK and the transcriptional effectors LIN-1/Ets and EOR-1. These results reveal multiple genetically separable roles for Ras signaling in tube development, as well as similarities to Ras-mediated control of branching morphogenesis in more complex organs, including the mammalian kidney. The relative simplicity of the excretory system makes it an attractive model for addressing basic questions about how cells gain or lose epithelial character and organize into tubular networks.

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    • "Our method is inexpensive and similar in technical complexity to laser ablation systems, which are used widely in studies of C. elegans (Fang-Yen et al. 2011), and therefore should extend readily to other transparent organisms such as embryos and larvae of Drosophila and zebrafish. We expect our method will be particularly useful in studying development, in which expression of transgenes with fine spatiotemporal control can help elucidate the cellular and molecular mechanisms governing cell fate decisions (Abdus-Saboor et al. 2011), body patterning (Pearson et al. 2005), and organogenesis (Mango 2009). "
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    G3-Genes Genomes Genetics 08/2013; 3(10). DOI:10.1534/g3.113.007682 · 3.20 Impact Factor
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    • "The Clr phenotype can be associated with defects in protein degradation in muscles (Szewczyk and Jacobson, 2003) and is reported to result from excessive FGFR/Ras/MAPK signaling (Kokel et al., 1998). However, decreased EGFR/Ras/MAPK activity in the excretory duct can also result in arrested Clr animals (Yochem et al., 1997; Abdus-Saboor et al., 2011). The Con phenotype is also linked to excessive Ras/MAPK signaling as implicated in the defense mechanism against pathogens (Nicholas and Hodgkin, 2004). "
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    ABSTRACT: The group I members of the Nm23 (non-metastatic) gene family encode nucleoside diphosphate kinases (NDPKs) that have been implicated in the regulation of cell migration, proliferation and differentiation. Despite their developmental and medical significance, the molecular functions of these NDPKs remain ill defined. To minimize confounding effects of functional compensation between closely related Nm23 family members, we studied ndk-1, the sole Caenorhabditis elegans ortholog of group I NDPKs, and focused on its role in Ras/mitogen-activated protein kinase (MAPK)-mediated signaling events during development. ndk-1 inactivation leads to a protruding vulva phenotype and affects vulval cell fate specification through the Ras/MAPK cascade. ndk-1 mutant worms show severe reduction of activated, diphosphorylated MAPK in somatic tissues, indicative of compromised Ras/MAPK signaling. A genetic epistasis analysis using the vulval induction system revealed that NDK-1 acts downstream of LIN-45/Raf, but upstream of MPK-1/MAPK, at the level of the kinase suppressors of ras (KSR-1/2). KSR proteins act as scaffolds facilitating Ras signaling events by tethering signaling components, and we suggest that NDK-1 modulates KSR activity through direct physical interaction. Our study reveals that C. elegans NDK-1/Nm23 influences differentiation by enhancing the level of Ras/MAPK signaling. These results might help to better understand how dysregulated Nm23 in humans contributes to tumorigenesis.
    Development 08/2013; 140(16):3486-95. DOI:10.1242/dev.094011 · 6.46 Impact Factor
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    • "Therefore, let-60/Ras loss-of-function mutants, which lack the excretory duct cell, die as " rod-like " L1 larvae with a turgid, fluid-filled appearance (Figure 3B). let-60/Ras gain-of-function mutants (which are viable) have two fused excretory duct cells (Yochem et al., 1997; Abdus-Saboor et al., 2011). The excretory duct cell was the sole lethal focus identified in a mosaic analysis of let-60 ras (Yochem et al., 1997). "
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    ABSTRACT: Receptor Tyrosine Kinase (RTK)-Ras-Extracellular signal-regulated kinase (ERK) signaling pathways control many aspects of C. elegans development and behavior. Studies in C. elegans helped elucidate the basic framework of the RTK-Ras-ERK pathway and continue to provide insights into its complex regulation, its biological roles, how it elicits cell-type appropriate responses, and how it interacts with other signaling pathways to do so. C. elegans studies have also revealed biological contexts in which alternative RTK- or Ras-dependent pathways are used instead of the canonical pathway.
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