A Role for Dynein in the Inhibition of Germ Cell Proliferative Fate

ABSTRACT During normal development as well as in diseased states such as cancer, extracellular “niches” often provide cues to proximal cells and activate intracellular pathways. Activation of such signaling pathways in turn instructs cellular proliferation and differentiation. In the Caenorhabditis elegans gonad, GLP-1/Notch signaling instructs germ line stem cells to self-renew through mitotic cell division. As germ cells progressively move out of the niche, they differentiate by entering meiosis and eventually form gametes. In this model system, we uncovered an unexpected role for the dynein motor complex in promoting normal differentiation of proliferating germ cells. We demonstrate that dynein light chain 1 (DLC-1) and its partner, dynein heavy chain 1, inhibit the proliferative cell fate, in part through regulation of METT-10, a conserved putative methyltransferase. We show that DLC-1 physically interacts with METT-10 and promotes both its overall levels and nuclear accumulation. Our results add a new dimension to the processes controlled by the dynein motor complex, demonstrating that dynein can act as an antiproliferative factor.

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Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors

Development ◽

10.1242/dev.124.4.925 ◽

1997 ◽

Vol 124 (4) ◽

pp. 925-936 ◽

Cited By ~ 20

Author(s):

L.W. Berry ◽

B. Westlund ◽

T. Schedl

Keyword(s):

Caenorhabditis Elegans ◽

Cell Fate ◽

Germ Cells ◽

Transmembrane Domain ◽

Germ Line ◽

Late Onset ◽

Family Members ◽

Mitotic Cell ◽

Tumor Formation ◽

Mutant Phenotypes

Caenorhabditis elegans germ-line proliferation is controlled by an inductive interaction between the somatic distal tip cell and the germ line. GLP-1, a member of the Notch family of transmembrane receptors, is required continuously in the germ line to transduce the proliferative signal. In the absence of GLP-1, all proliferative germ cells exit the mitotic cell cycle and enter meiotic prophase. We have characterized an activating mutation in glp-1, oz112gf, that has the opposite phenotype. Homozygous glp-1(oz112gf) hermaphrodites and males have a completely tumorous germ line in which germ cells never leave the mitotic cycle. In glp-1(oz112gf) heterozygotes, germ-line polarity is established correctly, but as adults age, the distal proliferative population expands leading to a late-onset tumorous phenotype. The mutant receptor is constitutively active, promoting proliferation in the absence of ligand. The normal distal-proximal spatial restriction of GLP-1 expression is lost in tumorous and late-onset tumorous animals; ectopically proliferating germ cells contain membrane-associated GLP-1. The correlation between proliferation and expression, both in wild-type where glp-1 signalling is limited by localized ligand and in glp-1(oz112gf) where signalling is ligand-independent, suggests that glp-1 signalling positively regulates GLP-1 expression. In addition to germ-line defects, glp-1(oz112gf) causes inappropriate vulval cell fate specification. A missense mutation in a conserved extracellular residue, Ser642, adjacent to the transmembrane domain, is sufficient to confer the glp-1(oz112gf) mutant phenotypes. Two mammalian Notch family members, TAN-1 and int-3, are proto-oncogenes. Thus, activating mutations in both invertebrate and vertebrate Notch family members can lead to tumor formation.

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The fog-3 gene and regulation of cell fate in the germ line of Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/139.2.561 ◽

1995 ◽

Vol 139 (2) ◽

pp. 561-577 ◽

Cited By ~ 4

Author(s):

R E Ellis ◽

J Kimble

Keyword(s):

Caenorhabditis Elegans ◽

Germ Cell ◽

Sexual Identity ◽

Cell Fate ◽

Germ Cells ◽

Regulatory Network ◽

Germ Line ◽

The Other ◽

Nematode Caenorhabditis Elegans ◽

Inhibitory Interactions

Abstract In the nematode Caenorhabditis elegans, germ cells normally adopt one of three fates: mitosis, spermatogenesis or oogenesis. We have identified and characterized the gene fog-3, which is required for germ cells to differentiate as sperm rather than as oocytes. Analysis of double mutants suggests that fog-3 is absolutely required for spermatogenesis and acts at the end of the regulatory hierarchy controlling sex determination for the germ line. By contrast, mutations in fog-3 do not alter the sexual identity of other tissues. We also have characterized the null phenotype of fog-1, another gene required for spermatogenesis; we demonstrate that it too controls the sexual identity of germ cells but not of other tissues. Finally, we have studied the interaction of these two fog genes with gld-1, a gene required for germ cells to undergo oogenesis rather than mitosis. On the basis of these results, we propose that germ-cell fate might be controlled by a set of inhibitory interactions among genes that specify one of three fates: mitosis, spermatogenesis or oogenesis. Such a regulatory network would link the adoption of one germ-cell fate to the suppression of the other two.

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Haploid expression of a unique c-abl transcript in the mouse male germ line.

Molecular and Cellular Biology ◽

10.1128/mcb.5.7.1791 ◽

1985 ◽

Vol 5 (7) ◽

pp. 1791-1794 ◽

Cited By ~ 76

Author(s):

C Ponzetto ◽

D J Wolgemuth

Keyword(s):

Molecular Weight ◽

Germ Cells ◽

Germ Line ◽

Low Molecular Weight ◽

Male Germ Line ◽

Predominant Species ◽

Testicular Cells ◽

Regulated Expression ◽

Immature Mouse ◽

Normal Differentiation

RNA from immature mouse testes was shown to lack a low-molecular-weight c-abl transcript previously noted to be the predominant species in adult testes. The developmental pattern of appearance of this c-abl variant was determined by analyzing RNA obtained from purified populations of testicular cells in different stages of spermatogenesis. The appearance of the c-abl testicular variant was coincident with the entry of the germ cells into their haploid state and suggested that the regulated expression of this proto-oncogene may be important in the normal differentiation of the male germ line.

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The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis

Development ◽

10.1242/dev.122.8.2437 ◽

1996 ◽

Vol 122 (8) ◽

pp. 2437-2447 ◽

Cited By ~ 18

Author(s):

P. Gonczy ◽

S. DiNardo

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Cell Fate ◽

Germ Cells ◽

Germ Line ◽

Lineage Tracing ◽

Somatic Stem Cells ◽

Daughter Cyst ◽

Cyst Cell ◽

Cyst Cells

Spermatogenesis relies on the function of germ-line stem cells, as a continuous supply of differentiated spermatids is produced throughout life. In Drosophila, there must also be somatic stem cells that produce the cyst cells that accompany germ cells throughout spermatogenesis. By lineage tracing, we demonstrate the existence of such somatic stem cells and confirm that of germ-line stem cells. The somatic stem cells likely correspond to the ultrastructurally described cyst progenitor cells. The stem cells for both the germ-line and cyst lineage are anchored around the hub of non-dividing somatic cells located at the testis tip. We then address whether germ cells regulate the behavior of somatic hub cells, cyst progenitors and their daughter cyst cells by analyzing cell proliferation and fate in testes in which the germ line has been genetically ablated. Daughter cyst cells, which normally withdraw from the cell cycle, continue to proliferate in the absence of germ cells. In addition, cells from the cyst lineage switch to the hub cell fate. Male-sterile alleles of chickadee and diaphanous, which are deficient in germ cells, exhibit similar cyst cell phenotypes. We conclude that signaling from germ cells regulates the proliferation and fate of cells in the somatic cyst lineage.

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Germ cells of the mammalian female: A limited or renewable resource?

Biology of Reproduction ◽

10.1093/biolre/ioab115 ◽

2021 ◽

Author(s):

Mathilde Hainaut ◽

Hugh J Clarke

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Germ Cells ◽

Germ Line ◽

Marker Gene ◽

Somatic Cells ◽

Renewable Resource ◽

Weight Of Evidence ◽

Fetal Life

Abstract In many non-mammalian organisms, a population of germ-line stem cells supports continuing production of gametes during most or all the life of the individual, and germ-line stem cells are also present and functional in male mammals. Traditionally, however, they have been thought not to exist in female mammals, who instead generate all their germ cells during fetal life. Over the last several years, this dogma has been challenged by several reports, while supported by others. We describe and compare these conflicting studies with the aim of understanding how they came to opposing conclusions. We first consider studies that, by examining marker-gene expression, the fate of genetically marked cells, and consequences of depleting the oocyte population, addressed whether ovaries of post-natal females contain oogonial stem cells (OSC) that give rise to new oocytes. We next discuss whether ovaries contain cells that, even if inactive under physiological conditions, nonetheless possess OSC properties that can be revealed through cell-culture. We then examine studies of whether cells harvested after long-term culture of cells obtained from ovaries can, following transplantation into ovaries of recipient females, give rise to oocytes and offspring. Finally, we note studies where somatic cells have been re-programmed to acquire a female germ-cell fate. We conclude that the weight of evidence strongly supports the traditional interpretation that germ-line stem cells do not exist post-natally in female mammals. However, the ability to generate germ cells from somatic cells in vitro establishes a method to generate new gametes from cells of post-natal mammalian females.

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Transformation of the germ line into muscle in mes-1 mutant embryos of C. elegans

Development ◽

10.1242/dev.121.9.2961 ◽

1995 ◽

Vol 121 (9) ◽

pp. 2961-2972 ◽

Cited By ~ 8

Author(s):

S. Strome ◽

P. Martin ◽

E. Schierenberg ◽

J. Paulsen

Keyword(s):

Cell Fate ◽

Germ Cells ◽

Germ Line ◽

Primordial Germ Cells ◽

Primordial Germ Cell ◽

Wild Type ◽

C Elegans ◽

Stem Cell Divisions ◽

Asymmetric Partitioning

Mutations in the maternal-effect sterile gene mes-1 cause the offspring of homozygous mutant mothers to develop into sterile adults. Lineage analysis revealed that mutant offspring are sterile because they fail to form primordial germ cells during embryogenesis. In wild-type embryos, the primordial germ cell P4 is generated via a series of four unequal stem-cell divisions of the zygote. mes-1 embryos display a premature and progressive loss of polarity in these divisions: P0 and P1 undergo apparently normal unequal divisions and cytoplasmic partitioning, but P2 (in some embryos) and P3 (in most embryos) display defects in cleavage asymmetry and fail to partition lineage-specific components to only one daughter cell. As an apparent consequence of these defects, P4 is transformed into a muscle precursor, like its somatic sister cell D, and generates up to 20 body muscle cells instead of germ cells. Our results show that the wild-type mes-1 gene participates in promoting unequal germ-line divisions and asymmetric partitioning events and thus the determination of cell fate in early C. elegans embryos.

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Transcription factor AP2 controls cnidarian germ cell induction

Science ◽

10.1126/science.aay6782 ◽

2020 ◽

Vol 367 (6479) ◽

pp. 757-762 ◽

Cited By ~ 4

Author(s):

Timothy Q. DuBuc ◽

Christine E. Schnitzler ◽

Eleni Chrysostomou ◽

Emma T. McMahon ◽

Febrimarsa ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Germ Cell ◽

Cell Fate ◽

Germ Cells ◽

Adult Stem Cells ◽

Germ Line ◽

Cell Induction ◽

Cell Commitment ◽

I Cells

Clonal animals do not sequester a germ line during embryogenesis. Instead, they have adult stem cells that contribute to somatic tissues or gametes. How germ fate is induced in these animals, and whether this process is related to bilaterian embryonic germline induction, is unknown. We show that transcription factor AP2 (Tfap2), a regulator of mammalian germ lines, acts to commit adult stem cells, known as i-cells, to the germ cell fate in the clonal cnidarian Hydractinia symbiolongicarpus. Tfap2 mutants lacked germ cells and gonads. Transplanted wild-type cells rescued gonad development but not germ cell induction in Tfap2 mutants. Forced expression of Tfap2 in i-cells converted them to germ cells. Therefore, Tfap2 is a regulator of germ cell commitment across germ line–sequestering and germ line–nonsequestering animals.

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DYNLRB1 is Essential for Dynein Mediated Transport and Neuronal Survival

10.1101/727016 ◽

2019 ◽

Author(s):

Marco Terenzio ◽

Agostina Di Pizio ◽

Ida Rishal ◽

Letizia Marvaldi ◽

Pierluigi Di Matteo ◽

...

Keyword(s):

Cytoplasmic Dynein ◽

Cell Periphery ◽

Dynein Light Chain ◽

Motor Complex ◽

Dynein Motor ◽

Selective Depletion ◽

Severe Impairment ◽

Accessory Subunit ◽

And Function

ABSTRACTThe cytoplasmic dynein motor complex transports essential signals and organelles from the cell periphery to perinuclear region, hence is critical for the survival and function of highly polarized cells such as neurons. Dynein Light Chain Roadblock-Type 1 (DYNLRB1) is thought to be an accessory subunit required for specific cargos, but here we show that it is essential for general dynein-mediated transport and sensory neuron survival. Homozygous Dynlrb1 null mice are not viable and die during early embryonic development. Furthermore, heterozygous or adult knockdown animals display reduced neuronal growth, and selective depletion of Dynlrb1 in proprioceptive neurons compromises their survival. Conditional depletion of Dynlrb1 in sensory neurons causes deficits in several signaling pathways, including β-catenin subcellular localization, and a severe impairment in the axonal transport of both lysosomes and retrograde signaling endosomes. Hence, DYNLRB1 is an essential component of the dynein complex.

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Specification of Germ Cell Fates by FOG-3 Has Been Conserved During Nematode Evolution

Genetics ◽

10.1093/genetics/158.4.1513 ◽

2001 ◽

Vol 158 (4) ◽

pp. 1513-1525 ◽

Cited By ~ 1

Author(s):

Pei-Jiun Chen ◽

Soochin Cho ◽

Suk-Won Jin ◽

Ronald E Ellis

Keyword(s):

Cell Fate ◽

Germ Cells ◽

Mating Systems ◽

Germ Line ◽

Model Organism ◽

Cell Fates ◽

C Elegans ◽

Rapid Changes ◽

Self Fertilization ◽

Sexual Traits

Abstract Rapid changes in sexual traits are ubiquitous in evolution. To analyze this phenomenon, we are studying species of the genus Caenorhabditis. These animals use one of two different mating systems—male/hermaphroditic, like the model organism Caenorhabditis elegans, or male/female, like C. remanei. Since hermaphrodites are essentially females that produce sperm for self-fertilization, elucidating the control of cell fate in the germ line in each species could provide the key to understanding how these mating systems evolved. In C. elegans, FOG-3 is required to specify that germ cells become sperm. Thus, we cloned its homologs from both C. remanei and C. briggsae. Each species produces a single homolog of FOG-3, and RNA-mediated interference indicates that FOG-3 functions in each species to specify that germ cells develop as sperm rather than as oocytes. What factors account for the different mating systems? Northern analyses and RT-PCR data reveal that the expression of fog-3 is always correlated with spermatogenesis. Since the promoters for all three fog-3 genes contain binding sites for the transcription factor TRA-1A and are capable of driving expression of fog-3 in C. elegans hermaphrodites, we propose that alterations in the upstream sex-determination pathway, perhaps acting through TRA-1A, allow spermatogenesis in C. elegans and C. briggsae XX larvae but not in C. remanei.

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