Abstract
BackgroundCaenorhabditis elegans can endure long periods of environmental stress by altering their development to execute a quiescent state called “dauer”. Previous work has implicated LKB1 - the causative gene in the autosomal dominant, cancer pre-disposing disease called Peutz-Jeghers Syndrome (PJS), and its downstream target AMPK, in the establishment of germline stem cell (GSC) quiescence during the dauer stage. Loss of function mutations in both LKB1/par-4 and AMPK/aak(0) result in untimely GSC proliferation during the onset of the dauer stage, although the molecular mechanism through which these factors regulate quiescence remains unclear. Curiously, the hyperplasia observed in par-4 mutants is more severe than AMPK-compromised dauer larvae, suggesting that par-4 has alternative downstream targets in addition to AMPK to regulate germline quiescence.ResultsWe conducted three genome-wide RNAi screens to identify potential downstream targets of the protein kinases PAR-4 and AMPK that mediate dauer-dependent GSC quiescence. First, we screened to identify genes that phenocopy the par-4-dependent hyperplasia when compromised by RNAi. Two additional RNAi screens were performed to identify genes that suppressed the germline hyperplasia in par-4 and aak(0) dauer larvae, respectively. Interestingly, a subset of the candidates we identified are involved in the regulation of cell polarity and cytoskeletal function downstream of par-4, in an AMPK-independent manner. Moreover, we show that par-4 temporally regulates actin cytoskeletal organization within the dauer germ line at the rachis-adjacent membrane, in an AMPK-independent manner.ConclusionOur data suggest that the regulation of the cytoskeleton and cell polarity may contribute significantly to the tumour suppressor function of LKB1/par-4.
Highlights
Caenorhabditis elegans can endure long periods of environmental stress by altering their development to execute a quiescent state called “dauer”
To better understand how germline stem cell cycle quiescence is regulated during periods of reduced insulin-like signalling, we performed three independent genome-wide RNAi screens based on feeding dsRNA corresponding to every predicted gene in C. elegans [22]
The activity of the identified genes would presumably be under LKB1/PAR-4 and/or AMP-activated protein kinase (AMPK)-mediated regulation, and in the absence of either of these genes the activity of these targets would go unchecked during the dauer stage
Summary
Caenorhabditis elegans can endure long periods of environmental stress by altering their development to execute a quiescent state called “dauer”. One of the defining features of any multicellular organism is their capacity to organize essentially identical cellular units into multiple individual cell types with distinct functional properties These cells will sort themselves to later give rise to the diverse tissues and organs that will function in a coordinated manner to support growth and reproduction. Tissues themselves must be polarized to provide structural integrity that is unique to their function, and for the correct partitioning of cellular constituents including intracellular proteins, organelles and cytoskeletal components [1] This permits cells to sense and Kadekar et al BMC Genomics (2018) 19:462 respond to spatiotemporal signals from adjacent cells and/or the surrounding microenvironment. Consistent with this, mutations in the polarity-regulating protein kinase LKB1/STK11 have been identified in individuals with Peutz-Jeghers Syndrome (PJS), an autosomal dominant disease that predisposes patients to various types of cancer [5, 6]
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