The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in Caenorhabditis elegans

摘要

Lipocalins are secreted cup-shaped glycoproteins that bind sterols, fatty acids, and other lipophilic molecules. Lipocalins have been implicated in a wide array of processes related to lipophilic cargo transport, sequestration, and signaling, and several are used as biomarkers for human disease, but the functions of most lipocalins remain poorly understood. Here we show that the Caenorhabditis elegans lipocalin [LPR-1][1] is required to maintain apical membrane integrity and a continuous lumen in two narrow unicellular tubes, the excretory duct and pore, during a period of rapid lumen elongation. [LPR-1][1] fusion protein is expressed by the duct and pore and accumulates both intracellularly and in apical extracellular compartments, but it can also function cell nonautonomously when provided from outside of the excretory system. [lpr-1][1] mutant defects can be rescued by increased signaling through the epidermal growth factor (EGF)-Ras-extracellular signal regulated kinase (ERK) pathway, which promotes the more elongated duct vs. less elongated pore tube fate. Spatial and temporal rescue experiments indicate that Ras signaling acts within the duct and pore tubes during or prior to cell fate determination to bypass the requirement for [LPR-1][1]. [lpr-1][1] mutations did not disrupt [LIN-3][2]/EGF-dependent duct-fate specification, prevent functioning of any specific [LIN-3][2]/EGF isoform, or alter [LET-23][3]/EGFR localization, and reduced signaling did not phenocopy or enhance [lpr-1][1] mutant defects. These data suggest that [LPR-1][1] protects lumen integrity through a [LIN-3][2]/EGF-independent mechanism, but that increased signaling upregulates some target(s) that can compensate for [lpr-1][1] absence. [1]: http://www.wormbase.org/db/get?name=WBGene00002393;class=Gene [2]: http://www.wormbase.org/db/get?name=WBGene00002992;class=Gene [3]: http://www.wormbase.org/db/get?name=WBGene00002299;class=Gene