Androwski, Rebecca J et al. (2015) International Worm Meeting "Role of autophagy in IL2 dendritic arbors during dauer formation and recovery."

Androwski, Rebecca J, Schroeder, Nathan E, Flatt, Kristen M

[International Worm Meeting, 2015]

When grown under conditions of low food, high temperature and high population density, C. elegans larvae will develop through an alternative, adaptive stage called dauer. While in dauer the larva show changes in behavior and morphology. For example, we have shown six Inner Labial 2 (IL2) neurons undergo dramatic reorganization during dauer1. IL2 quadrant (IL2Q) neurons arborize extensively during dauer and resorb their branches upon recovery from dauer. Moreover animals which have passed through dauer as part of development show several differences during adulthood in comparison to adults which have not experienced dauer. We show the IL2Q neurons resorb the bulk of their branches but remnant branches remain in post-dauer adults. This unique feature of IL2Q branching provides us with a model for testing proteins that help the cell recover from stress. We address the question of how the IL2Q neurons show a three-fold increase in dendritic length, which is maintained throughout dauer, when the worm is trying to conserve energy. We are examining the role of autophagy in IL2 branching. Autophagy which is upregulated during dauer, is a mechanism through which the cell degrades intracellular components and is widely conserved across species. Autophagy is an adaptive stress response that promotes survival under adverse conditions. C. elegans orthologues to yeast autophagy proteins are critical for both C.elegans autophagy and dauer formation.2 The basic steps of autophagy include vesicle nucleation, vesicle elongation, docking with the lysosome, and vesicle breakdown and degradation. We found that LGG-1::gfp, a widely used marker for autophagy, is expressed in the IL2s during dauer . We can use the temporal expression of LGG-1 to determine at which time points during dauer formation and recovery autophagy is upregulated in the IL2 neurons. Additionally we are assessing unc-51 mutants for IL2 branching and branch recovery defects; UNC-51 is involved in induction of autophagy. unc-51 animals have been described as forming 70% abnormal dauers2 - to address differential dauer formation, we are examining IL2 arbors in both abnormal and normally formed dauers. 1)Schroeder NE, Androwski RJ, Rashid A, Lee H, Lee J, Barr MM. Curr Biol. 2013 Aug 19;23(16):1527-35.2)Melendez A1, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Science. 2003 Sep 5;301(5638):1387-91.

Hughes, K. et al. (2019) International Worm Meeting "Physical exertion exacerbates deterioration in an animal model of Duchenne muscular dystrophy."

Rodriguez, Anjelica, Vemuri, Samantha, Barickman, Lucas, Andriulis, Victoria, Flatt, Kristen, Vidal-Gadea, Andres, Ray, Sneha, Niswonger, Dana, Gutta, Neha, Stein, Wolfgang, Hughes, K., Veerappan, Visalakshi, Schroeder, Nathan, Singhvi, Aakanksha, Kullman, Alex, Lim, Calis, Rodemoyer, Brian, Schuler, Andrew, Cuciarone, Kori

[International Worm Meeting, 2019]

Duchenne muscular dystrophy (DMD) is a genetic disorder caused by loss of dystrophin, responsible for connecting actin to the sarcolemma and transferring force into the extracellular matrix. In humans, DMD presents at a young age, resulting in developmental delays, muscle necrosis, increased sarcoplasmic calcium, loss of ambulation, and early death. Current animal models are unable to model the severity of DMD without the addition of sensitizing mutations. Thus, it remains elusive if increased sarcoplasmic calcium observed in dystrophic muscles follows or leads the mechanical insults caused by the muscle's disrupted contractile machinery. This knowledge has important implications for patients, as physiotherapeutic treatments may either help or exacerbate symptoms, depending on how dystrophic muscles differ from healthy ones. We observe that sarcoplasmic calcium dysregulation in dys-1 worms precedes overt structural phenotypes and can be mitigated by silencing calmodulin expression. Recently, we showed that burrowing dystrophic (dys-1) worms recapitulate many salient phenotypes of DMD. Here, we report dys-1 worms display early pathogenesis and increased lethality. To learn how dystrophic musculature responds to altered physical activity, we cultivated dys-1 animals in environments requiring either high intensity or high frequency muscle exertion during locomotion. We find that several muscular parameters (such as size) improve with increased activity. However, longevity in dystrophic animals was negatively associated with muscular exertion regardless of the duration of the effort. The high degree of phenotypic conservation between dystrophic worms and humans provides a unique opportunity to gain insights into DMD's underlying pathology and to assess potential treatment strategies.