Da Cunha, Dayse, Melendez, Alicia, Ames, Kristina, Gonzalez, Brenda, Lin, Feng, Bulow, Hannes, Konta, Marina, Shechter, Gabriel, Wong, Sara, Starikov, Lev
[
International Worm Meeting,
2017]
Autophagy is a conserved cellular recycling process crucial for cellular homeostasis. In a multistep process, cellular material destined for degradation is enclosed in an organelle with a double-membrane, the autophagosome, which in turn fuses with the lysosome. BEC-1, the C. elegans ortholog of Beclin1/BECN1 in mammals, was shown to be a haploinsufficient tumor suppressor protein in mammals, crucial for the initial nucleation step of autophagosome formation. In previous studies we showed that BEC-1 serves important functions during development, and longevity of multicellular organisms. In addition, we demonstrated a role for BEC-1 in endocytosis, including in retromer transport from endosome to Golgi, and lipid homeostasis. We now describe a novel role for BEC-1 and autophagy in germ line stem cell homeostasis. The decision of a stem cell to proliferate or differentiate is finely controlled, and several pathways, such as GLP-1/Notch, DAF-2/ insulin IGF-1 receptor (IIR), and DAF-7/TGF beta signaling have been shown to be required for the proper number of germline progenitors. We found that BEC-1, and several other autophagy proteins, such as ATG-18 (in mammals WIPI1/2), ATG-16.2 (in mammals ATG16L) and ATG-7 (in mammals ATG7) are required for the late larval expansion of germline stem cell progenitors during development. Interestingly, BEC-1, ATG-18, and ATG-16.2 act independently of the GLP-1/Notch or DAF-7/TGF beta pathways, but upstream of the DAF-2/insulin IGF-1 receptor (IIR) signaling pathway, to promote germline stem cell proliferation. BEC-1, ATG-18, and ATG-16.2, all promote cell cycle progression and are negatively regulated by DAF-18/PTEN, similar to DAF-2/IIR. However, whereas BEC-1 acts through SKN-1/Nrf1, ATG-18 and ATG-16.2 act through the DAF-16/FOXO transcription factor. In contrast, ATG-7 functions together with the DAF-7/TGF beta pathway, to promote germline proliferation, and is not required for cell cycle progression. Interestingly, BEC-1/Beclin1 functions cell non-autonomously to facilitate cell cycle progression and stem cell proliferation. Thus, our findings demonstrate a novel, non-autonomous role for BEC-1 in the control of stem cell proliferation, and cell cycle progression.
[
International Worm Meeting,
2011]
Nematodes are well suited for a comparative study of early embryogenesis. Analyzing development of a single model system like Caenorhabditis elegans does not shed any light on the degree of evolutionary modifications within the taxon Nematoda. For better understanding evolution of development among nematodes including the identification of plesiomorphic and apomorphic characters, we compared early embryogenesis of representatives from all 12 nematode clades (phylogeny after Holterman et al., 2006; Mol. Biol. Evol. 23:1792-1800). Our data reveal that embryogenesis is unexpectedly variable with floating transitions that can be interpreted as frozen images of evolutionary change. Particularly, members of clade 1 and 2 differ massively from the standard C. elegans. Nevertheless, some basic developmental similarities appear to be common among all nematodes, e.g. the general existence of at least partial cell lineages and the influence of Polarity Organizing Centers (POCs). These POCs are required for generating a linear sequence of cells along the a-p axis which constitute the ventral midline. Depending on phylogenetic position fewer or more cells of this midline divide into left and right daughters this way establishing bilateral symmetry within individual lineages. Our studies reveal the stepwise emergence of founder cells and dramatic fate shifts during evolution. The comparison between embryogenesis of the basal nematode Tobrilus stefanskii and the tardigrade Hypsibius dujardini (Gabriel et al., 2007; Dev. Biol. 312, 545-59) with respect to the early cell division pattern revealed surprising similarities between these two. This may be considered as embryological support for the Ecdysozoa hypothesis.