title: A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development.
abstract: 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-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/BECN1/Beclin1 acts independently of the GLP-1/Notch or DAF-7/TGF-β 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, ATG-18/WIPI1/2, 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/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/TGF-β 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.
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA; The Graduate Center of the City University of New York, New York, NY 10016, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Ames
authors.affiliation: The Graduate Center of the City University of New York, New York, NY 10016, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Dayse S
authors.initials: DS
authors.lastname: Da Cunha
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Gonzalez
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konta
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Shechter
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA.
authors.forename: Lev
authors.initials: L
authors.lastname: Starikov
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Wong
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Hannes E
authors.initials: HE
authors.lastname: Bülow
authors.affiliation: Queens College, The City University of New York, Flushing, NY 11367, USA; The Graduate Center of the City University of New York, New York, NY 10016, USA. Electronic address: alicia.melendez@qc.cuny.edu.
authors.forename: Alicia
authors.initials: A
authors.lastname: Meléndez
mesh_terms: D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division; D049109:Cell Proliferation; D005854:Germ Cells / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D033921:Vesicular Transport Proteins; C477268:bec-1 protein, C elegans
keywords: C. elegans; atg-16.2; atg-7; autophagy; bec-1; cell cycle; germline; stem cell