scholarly journals Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma of C. elegans

2021 ◽  
Vol 7 (26) ◽  
pp. eabg3012
Author(s):  
Giuseppe Calculli ◽  
Hyun Ju Lee ◽  
Koning Shen ◽  
Uyen Pham ◽  
Marija Herholz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Aggregation ◽  
Germ Line ◽  
Wnt Signaling Pathway ◽  
Germline Stem Cells ◽  
C Elegans ◽  
Unfolded Protein ◽  
Somatic Tissues ◽  
Intracellular Changes ◽  
The Unfolded Protein Response

Protein aggregation causes intracellular changes in neurons, which elicit signals to modulate proteostasis in the periphery. Beyond the nervous system, a fundamental question is whether other organs also communicate their proteostasis status to distal tissues. Here, we examine whether proteostasis of the germ line influences somatic tissues. To this end, we induce aggregation of germline-specific PGL-1 protein in germline stem cells of Caenorhabditis elegans. Besides altering the intracellular mitochondrial network of germline cells, PGL-1 aggregation also reduces the mitochondrial content of somatic tissues through long-range Wnt signaling pathway. This process induces the unfolded protein response of the mitochondria in the soma, promoting somatic mitochondrial fragmentation and aggregation of proteins linked with neurodegenerative diseases such as Huntington’s and amyotrophic lateral sclerosis. Thus, the proteostasis status of germline stem cells coordinates mitochondrial networks and protein aggregation through the organism.

scholarly journals Cellular Analyses of the Mitotic Region in the Caenorhabditis elegans Adult Germ Line

2006 ◽  
Vol 17 (7) ◽  
pp. 3051-3061 ◽  
Author(s):  
Sarah L. Crittenden ◽  
Kimberly A. Leonhard ◽  
Dana T. Byrd ◽  
Judith Kimble
Keyword(s):  
Stem Cells ◽  
Caenorhabditis Elegans ◽  
Germ Cells ◽  
Germ Line ◽  
Germline Stem Cells ◽  
C Elegans ◽  
Brdu Label ◽  
Asymmetric Divisions ◽  
Brdu Labeling ◽  
Cell Niche

The Caenorhabditis elegans germ line provides a model for understanding how signaling from a stem cell niche promotes continued mitotic divisions at the expense of differentiation. Here we report cellular analyses designed to identify germline stem cells within the germline mitotic region of adult hermaphrodites. Our results support several conclusions. First, all germ cells within the mitotic region are actively cycling, as visualized by bromodeoxyuridine (BrdU) labeling. No quiescent cells were found. Second, germ cells in the mitotic region lose BrdU label uniformly, either by movement of labeled cells into the meiotic region or by dilution, probably due to replication. No label-retaining cells were found in the mitotic region. Third, the distal tip cell niche extends processes that nearly encircle adjacent germ cells, a phenomenon that is likely to anchor the distal-most germ cells within the niche. Fourth, germline mitoses are not oriented reproducibly, even within the immediate confines of the niche. We propose that germ cells in the distal-most rows of the mitotic region serve as stem cells and more proximal germ cells embark on the path to differentiation. We also propose that C. elegans adult germline stem cells are maintained by proximity to the niche rather than by programmed asymmetric divisions.

scholarly journals HSP-4/BiP expression in secretory cells is regulated by a lineage-dependent differentiation program and not by the unfolded protein response

2018 ◽  
Author(s):  
Ji Zha ◽  
Jasmine Alexander-Floyd ◽  
Tali Gidalevitz
Keyword(s):  
Unfolded Protein Response ◽  
Secretory Cells ◽  
C Elegans ◽  
Unfolded Protein ◽  
Daughter Cells ◽  
Developmental Program ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response ◽  
Anticipatory Activation

AbstractDifferentiation of secretory cells leads to sharp increases in protein synthesis, challenging ER proteostasis. Anticipatory activation of the unfolded protein response (UPR) prepares cells for the onset of secretory function by expanding the ER size and folding capacity. How cells ensure that the repertoire of induced chaperones matches their post-differentiation folding needs is not well understood. We find that during differentiation of stem-like seam cells, a typical UPR target, the C. elegans BiP homologue HSP-4, is selectively induced in alae-secreting daughter cells, but is repressed in hypodermal daughter cells. Surprisingly, this lineage-dependent induction bypasses the requirement for UPR signaling, and instead is controlled by a specific developmental program. The repression of HSP-4 in hypodermal-fated cells requires a transcriptional regulator BLMP-1/BLIMP1, involved in differentiation of mammalian secretory cells. The HSP-4 induction is anticipatory, and is required for the integrity of secreted alae. Thus, differentiation programs can directly control a broad-specificity chaperone that is normally stress-dependent, to ensure the integrity of secreted proteins.

scholarly journals ER stress causes widespread protein aggregation and prion formation

2017 ◽  
Vol 216 (8) ◽  
pp. 2295-2304 ◽  
Author(s):  
Norfadilah Hamdan ◽  
Paraskevi Kritsiligkou ◽  
Chris M. Grant
Keyword(s):  
Protein Aggregation ◽  
Er Stress ◽  
Secretory Pathway ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

scholarly journals Loss of foxo rescues stem cell aging in Drosophila germ line

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Filippo Artoni ◽  
Rebecca E Kreipke ◽  
Ondina Palmeira ◽  
Connor Dixon ◽  
Zachary Goldberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Ionizing Radiation ◽  
Cell Injury ◽  
Germ Line ◽  
Adult Stem Cell ◽  
Cell Aging ◽  
Germline Stem Cells ◽  
Cell Cycle Reentry

Aging stem cells lose the capacity to properly respond to injury and regenerate their residing tissues. Here, we utilized the ability of Drosophila melanogaster germline stem cells (GSCs) to survive exposure to low doses of ionizing radiation (IR) as a model of adult stem cell injury and identified a regeneration defect in aging GSCs: while aging GSCs survive exposure to IR, they fail to reenter the cell cycle and regenerate the germline in a timely manner. Mechanistically, we identify foxo and mTOR homologue, Tor as important regulators of GSC quiescence following exposure to ionizing radiation. foxo is required for entry in quiescence, while Tor is essential for cell cycle reentry. Importantly, we further show that the lack of regeneration in aging germ line stem cells after IR can be rescued by loss of foxo.

scholarly journals Stem Cells: Muscle Cells Enwrap Escaped Germline Stem Cells in C. elegans

2019 ◽  
Vol 29 (5) ◽  
pp. R150-R152
Author(s):  
Charlotte A. Kelley ◽  
Erin J. Cram
Keyword(s):  
Stem Cells ◽  
Muscle Cells ◽  
Germline Stem Cells ◽  
C Elegans

scholarly journals Regulation of the mitosis/meiosis decision in the Caenorhabditis elegans germline

2003 ◽  
Vol 358 (1436) ◽  
pp. 1359-1362 ◽  
Author(s):  
Sarah L. Crittenden ◽  
Christian R. Eckmann ◽  
Liaoteng Wang ◽  
David S. Bernstein ◽  
Marvin Wickens ◽  
...  
Keyword(s):  
Stem Cells ◽  
Caenorhabditis Elegans ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Germline Stem Cells ◽  
Puf Proteins ◽  
C Elegans ◽  
Transcriptional Regulatory ◽  
Mitotic Proliferation ◽  
Multicellular Organisms

During the development of multicellular organisms, the processes of growth and differentiation are kept in balance to generate and maintain tissues and organs of the correct size, shape and cellular composition. We have investigated the molecular controls of growth and differentiation in the Caenorhabditis elegans germline. A single somatic cell, called the distal tip cell, promotes mitotic proliferation in the adjacent germline by GLP–1/Notch signalling. Within the germline, the decisions between mitosis and meiosis and between spermatogenesis and oogenesis are controlled by a group of conserved RNA regulators. FBF, a member of the PUF (for Pumilio and FBF) family of RNA–binding proteins, promotes mitosis by repressing gld–1 mRNA activity; the GLD–1, GLD–2, GLD–3 and NOS–3 proteins promote entry into meiosis by regulating mRNAs that remain unknown. The regulatory balance between opposing FBF and GLD activities is crucial for controlling the extent of germline proliferation. PUF proteins regulate germline stem cells in both Drosophila and C. elegans and are localized to germline stem cells of the mammalian testis. Therefore, this post–transcriptional regulatory switch may be an ancient mechanism for controlling maintenance of stem cells versus differentiation.

scholarly journals CENP-C regulates centromere assembly, asymmetry and epigenetic age in Drosophila germline stem cells

2020 ◽  
Author(s):  
Ben L Carty ◽  
Anna A Dattoli ◽  
Elaine M Dunleavy
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Germ Line ◽  
Asymmetric Distribution ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Sister Chromatids ◽  
Asymmetric Divisions ◽  
Centromere Assembly

AbstractGermline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies) - the epigenetic determinant of centromere identity - is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of ‘mitotic drive’ that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

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