A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development

The decision of stem cells to proliferate and differentiate is finely controlled. The Caenorhabditis elegans germline provides a tractable system for studying the mechanisms that control stem cell proliferation and homeostasis [1-4]. Autophagy is a conserved cellular recycling process crucial for cellular homeostasis in many different contexts [5], but its function in germline stem cell proliferation remains poorly understood. Here, we describe a function for autophagy in germline stem cell proliferation. We found that autophagy genes such as bec-1/BECN1/Beclin1, atg-162/ATG16L,atg18/WIPI1/2, and atg-7/ATG7 are required for the late larval expansion of germline stem cell progenitors in the C. elegans gonad. We further show that BEC-1/BECN1/Beclinl acts independently of the GLP-1/Notch or DAF-7/TGF-13 pathways but together with the DAF-2/insulin IGF-1 receptor (IIR) signaling pathway to promote germline stem cell proliferation. Similar to DAF-2/IIR, BEC-1/BECN1/Beclin1, ATG18/WIP11 /2, and ATG-16.2/ATG16L all promote cell cycle progression and are negatively regulated by the phosphatase and tensin homolog DAF-18/PTEN. However, whereas BEC-1/BECN1/Beclin1 acts through the transcriptional regulator SKN-1/Nrf1, ATG-18/WIP11/2 and ATG-16.2/ATG16L exert their function through the DAF-16/FOX0 transcription factor. In contrast, ATG-7 functions in concert with the DAF-7/TGF-f3 pathway to promote germline proliferation and is not required for cell -cycle progression. Finally, we report that BEC-1/BECN1/Beclin1 functions non -cell -autonomously to facilitate cell -cycle progression and stem cell proliferation. Our findings demonstrate a novel non -autonomous role for BEC-1/BECN1/Beclin1 in the control of stem cell proliferation and cell -cycle progression, which may have implications for the understanding and development of therapies against malignant cell growth in the future.