Sex-Determination and WNT Pathways Regulate Developmental Muscle Remodeling in C. elegans
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In response to altered physiological demands, cardiac muscles remodel their muscle mass and contractile properties to sustain muscle performance. However, dramatic alterations of the sarcomere structure are rarely observed in mammalian models. I studied the C. elegans anal depressor development in males and hermaphrodites, to address how a differentiated muscle cell sex-specifically remodels to achieve sarcomere rearrangement and functional alterations. In both larval males and hermaphrodites, the anal depressor muscle possesses a dorsal-ventrally oriented sarcomere. The contraction of the muscle cell facilitates defecation behavior. However, in adult males, the anal depressor reorganizes its sarcomere and becomes a copulation muscle. To identify the cytoskeletal alteration events, as well as the sex-determination mechanism that contribute to the sarcomere rearrangement, I used YFP:actin to monitor, and mutant analysis, laser-ablation and transgenic feminization to perturb the cell's morphological dynamics. In young larva, the muscle of both sexes has similar sarcomere morphology. However later in L4, the male extrinsic sex mechanism promotes formation of a ventral slit, demarcating the sarcomere into anterior and posterior half. The male intrinsic sex determination mechanism then promotes the disassembly of sarcomere. Finally, the anterior domain establishes a novel ventral attachment to the sex muscles, and reassembles an anterior-posteriorly oriented sarcomere. To identify the signaling pathways that are sex-differentially activated to promote sarcomere disassembly, I first examined a series of Wnt-canonical mutants. egl- 20, lin-44, lin-17 and bar-1 mutants possess sarcomere disassembly defects. However, the incomplete penetrance of the Wnt mutants suggests the involvement of parallel mechanisms. Through forward genetics, I isolated a nonsense mutation in egl-8/phospholipase C-β, which potentially perturbs the calcium signaling in the anal depressor. Mutant analysis of goa-1/Gα, itr-1/IP3R, and unc-68/RyR suggests the positive role of Wnt-calcium pathway in regulating the sarcomere disassembly process. By monitoring the calcium dynamics in the anal depressor, I found that the calcium signaling is active during L4 development, to activate a group of proteases (clp-6/Calpain) and phosphatase (tax-6/Calcineurin). Monitoring BAR-1 activity in the anal depressor suggests an active role of β-catenin signaling during early development. Therefore, Wnt-β-catenin and Wnt-calcium pathway function during different development stages to regulate anal depressor remodeling.
Chen, Xin (2016). Sex-Determination and WNT Pathways Regulate Developmental Muscle Remodeling in C. elegans. Doctoral dissertation, Texas A & M University. Available electronically from