| Popis: |
The decision of stem cells to proliferate and differentiate is finely controlled. The Caenorhabditis elegans germ line provides a tractable system to study 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/Beclin1, atg-16.2/ATG16L, atg-18/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/Beclin1 acts independently of the GLP-1/Notch or DAF-7/TGFβ 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/Beclin1, ATG-18/WIPI1/2 and ATG-16.2/ATG16L all promote cell cycle progression, and are negatively regulated by the phosphatase and tensin DAF-18/PTEN. However, whereas BEC-1/Beclin1 acts through the transcriptional regulator SKN-1/Nrf1, ATG-18/WIPI1/2 and ATG-16.2/ATG16L exert their function through the DAF-16/FOXO transcription factor. In contrast, ATG-7 functions in concert with the DAF-7/ TGFβ pathway to promote germline proliferation, and is not required for cell cycle progression. Finally, we report that BEC-1/Beclin1 functions cell non-autonomously to facilitate cell cycle progression and stem cell proliferation. Our findings demonstrate a novel non-autonomous role for BEC-1/Beclin1 in the control 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. |
