Scratching the niche that controls Caenorhabditis elegans germline stem cells

doi:10.1016/j.semcdb.2009.09.005

Seminars in Cell & Developmental Biology

Volume 20, Issue 9, December 2009, Pages 1107-1113

https://doi.org/10.1016/j.semcdb.2009.09.005 Get rights and content

Abstract

The Caenorhabditis elegans gonad provides a well-defined model for a stem cell niche and its control of self-renewal and differentiation. The distal tip cell (DTC) forms a mesenchymal niche that controls germline stem cells (GSCs), both to generate the germline tissue during development and to maintain it during adulthood. The DTC uses GLP-1/Notch signaling to regulate GSCs; germ cells respond to Notch signaling with a network of RNA regulators to control the decision between self-renewal and entry into the meiotic cell cycle.

Introduction

Stem cells are widely used in multicellular organisms, both to generate tissues during development and to maintain them during adulthood. One major control of stem cells is their niche, which is the microenvironment that surrounds and maintains them. This concept was put forward over 30 years ago [1], and the first niche was identified soon thereafter [2]. Since those early days, tremendous progress has been made analyzing a variety of stem cell niches in multiple organisms, including both animals and plants [3], [4], [5].

Our review focuses on the stem cell niche for GSCs in Caenorhabditis elegans. This well-defined niche is formed by a mesenchymal cell, the distal tip cell (DTC). We begin by introducing the system and basic concepts critical to this system. We then review molecular controls that are responsible for generating and maintaining the DTC niche itself as well as molecular controls used by the DTC niche to control the decision between germline self-renewal and differentiation, both during development and in adults.

Section snippets

The distal tip cell provides a niche for germline stem cells

The cellular simplicity and genetic tractability of C. elegans contributed greatly to early identification of the DTC cellular niche and its use of Notch signaling for GSC maintenance. In this section, we provide essential background on the C. elegans germline and briefly review evidence that the DTC and Notch signaling regulate GSCs and germline self-renewal. We also include more recent studies that begin to delineate the DTC and its function in more depth. Importantly, Notch signaling is now

Molecular controls of niche specification and maintenance

The size and strength of a stem cell niche affects stem cells [41], [42], [43], [44]. Therefore, it is critical to know how the stem cell niche itself is specified and maintained. Regulation of the DTC has now been worked out in some detail, and at least some of those controls are likely to be conserved in other animals.

Germ cell intrinsic controls of self-renewal

Downstream of Notch signaling, a network of RNA regulators functions within germ cells to control their decision between self-renewal and early differentiation. This network has been described in detail elsewhere [3]. Here we focus on stem cell control by two PUF RNA-binding proteins, which are conserved stem cell regulators [58], but best understood in C. elegans.

Conclusions and future directions

Stem cells are controlled by both extrinsic and intrinsic factors. In the C. elegans germline, the DTC provides a cellular stem cell niche that maintains germline self-renewal via the GLP-1/Notch signaling pathway. The Wnt pathway and CEH-22/Nkx2.5 specify the DTC fate and HLH-2/E/da maintains DTC niche function. Many conserved RNA regulators act intrinsically within the germline tissue to control self-renewal and differentiation, including meiotic entry and the sperm/oocyte fate decision. In

Acknowledgements

We thank A. Helsley and L. Vanderploeg for their help in preparing the manuscript and figures. We also thank members of the Kimble lab, especially S. Crittenden, for helpful discussions, and S. Crittenden, K. Knobel, C. Stumpf and D. Greenstein for providing comments on the manuscript. D.T.B. was supported by NIH postdoctoral fellowship F32 GM072126. J.K. is an investigator of the Howard Hughes Medical Institute.

References (81)

J.E. Kimble et al.
On the control of germ cell development in Caenorhabditis elegans
Dev Biol
(1981)
J.R. Dinneny et al.
Plant stem cell niches: standing the test of time
Cell
(2008)
A. Jaramillo-Lambert et al.
Differential timing of S phases, X chromosome replication, and meiotic prophase in the C. elegans germ line
Dev Biol
(2007)
A.R. Kidd et al.
A β-catenin identified by functional rather than sequence criteria and its role in Wnt/MAPK signaling
Cell
(2005)
N. Lam et al.
Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans
Curr Biol
(2006)
J. Austin et al.
glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans
Cell
(1987)
G. Seydoux et al.
Cell-cell interactions prevent a potential inductive interaction between soma and germline in C. elegans
Cell
(1990)
A.S. Pepper et al.
The establishment of Caenorhabditis elegans germline pattern is controlled by overlapping proximal and distal somatic gonad signals
Dev Biol
(2003)
D.H. Hall et al.
Ultrastructural features of the adult hermaphrodite gonad of Caenorhabditis elegans: relations between the germ line and soma
Dev Biol
(1999)
F.P. Finger et al.
A role for septins in cellular and axonal migration in C. elegans
Dev Biol
(2003)

C.A. Horvath et al.

Epsin: inducing membrane curvature

Int J Biochem Cell Biol

(2007)

J. Kim et al.

Structural basis for endosomal targeting by the Bro1 domain

Dev Cell

(2005)

D. Hesselson et al.

GON-1 and fibulin have antagonistic roles in control of organ shape

Curr Biol

(2004)

Y. Kubota et al.

A fibulin-1 homolog interacts with an ADAM protease that controls cell migration in C. elegans

Curr Biol

(2004)

E.M. Hedgecock et al.

The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans

Neuron

(1990)

E.J. Ward et al.

Stem cells signal to the niche through the Notch pathway in the Drosophila ovary

Curr Biol

(2006)

J. Kimble et al.

The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans

Dev Biol

(1979)

K. Mizumoto et al.

Two βs or not two βs: regulation of asymmetric division by β-catenin

Trends Cell Biol

(2007)

B.T. Phillips et al.

A new look at TCF and β-catenin through the lens of a divergent C. elegans Wnt pathway

Dev Cell

(2009)

M. Asahina et al.

Crosstalk between a nuclear receptor and β-catenin signaling decides cell fates in the C. elegans somatic gonad

Dev Cell

(2006)

X. Karp et al.

Multiple roles for the E/Daughterless ortholog HLH-2 during C. elegans gonadogenesis

Dev Biol

(2004)

M.A. Chesney et al.

C. elegans HLH-2/E/Daughterless controls key regulatory cells during gonadogenesis

Dev Biol

(2009)

H. Terami et al.

Wnt11 facilitates embryonic stem cell differentiation to Nkx2.5-positive cardiomyocytes

Biochem Biophys Res Commun

(2004)

M.J. Kiel et al.

SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells

Cell

(2005)

M. Wickens et al.

A PUF family portrait: 3′UTR regulation as a way of life

Trends Genet

(2002)

S.W. Jin et al.

Regulation of cell fate in Caenorhabditis elegans by a novel cytoplasmic polyadenylation element binding protein

Dev Biol

(2001)

L.B. Lamont et al.

FBF-1 and FBF-2 regulate the size of the mitotic region in the C. elegans germline

Dev Cell

(2004)

C. Merritt et al.

3′ UTRs are the primary regulators of gene expression in the C. elegans germline

Curr Biol

(2008)

J.A. Kaye et al.

A 3′UTR pumilio-binding element directs translational activation in olfactory sensory neurons

Neuron

(2009)

C.R. Eckmann et al.

GLD-3, a Bicaudal-C homolog that inhibits FBF to control germline sex determination in C. elegans

Dev Cell

(2002)

J. McCarter et al.

Soma-germ cell interactions in Caenorhabditis elegans: multiple events of hermaphrodite germline development require the somatic sheath and spermathecal lineages

Dev Biol

(1997)

D.J. Killian et al.

Caenorhabditis elegans germline patterning requires coordinated development of the somatic gonadal sheath and the germ line

Dev Biol

(2005)

G. Kao et al.

The role of the laminin β subunit in laminin heterotrimer assembly and basement membrane function and development in C. elegans

Dev Biol

(2006)

M. Merris et al.

Sterol effects and sites of sterol accumulation in Caenorhabditis elegans: developmental requirement for 4α-methyl sterols

J Lipid Res

(2003)

R. Schofield

The relationship between the spleen colony-forming cell and the haemopoietic stem cell

Blood Cells

(1978)

J. Kimble et al.

Controls of germline stem cells, entry into meiosis, and the sperm/oocyte decision in Caenorhabditis elegans

Annu Rev Cell Dev Biol

(2007)

T. Xie et al.

Stem cells and their niche: an inseparable relationship

Development

(2007)

S. Chiba

Notch signaling in stem cell systems

Stem Cells

(2006)

S.L. Crittenden et al.

Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line

Mol Biol Cell

(2006)

D. Hansen et al.

Control of the proliferation versus meiotic development decision in the C. elegans germline through regulation of GLD-1 protein accumulation

Development

(2004)

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Citation Excerpt :
In C. elegans, germline stem cells are maintained by a single-cell niche, called the distal tip cell (DTC) (Kimble and White, 1981). The DTC extends elaborate processes in young adults that contact germ progenitor cells (stem cells and their proliferative and early-differentiating progeny) (Byrd and Kimble, 2009; Byrd et al., 2014; Cinquin et al., 2015; Crittenden et al., 2017; Lee et al., 2016; Wong et al., 2013). In the distal-most region of the gonad where the germ stem cells reside, the DTC extends elaborate processes that enwrap these cells, forming what has been termed the DTC plexus (Byrd et al., 2014; Lee et al., 2016).
Many stem cell niches contain support cells that increase contact with stem cells by enwrapping them in cellular processes. One example is the germ stem cell niche in C. elegans, which is composed of a single niche cell termed the distal tip cell (DTC) that extends cellular processes, constructing an elaborate plexus that enwraps germ stem cells. To identify genes required for plexus formation and to explore the function of this specialized enwrapping behavior, a series of targeted and tissue-specific RNAi screens were performed. Here we identify genes that promote stem cell enwrapment by the DTC plexus, including a set that specifically functions within the DTC, such as the chromatin modifier lin-40/MTA1, and others that act within the germline, such as the 14-3-3 signaling protein par-5. Analysis of genes that function within the germline to mediate plexus development reveal that they are required for expansion of the germ progenitor zone, supporting the emerging idea that germ stem cells signal to the niche to stimulate enwrapping behavior. Examination of wild-type animals with asymmetric plexus formation and animals with reduced DTC plexus elaboration via loss of two candidates including lin-40 indicate that cellular enwrapment promotes GLP-1/Notch signaling and germ stem cell fate. Together, our work identifies novel regulators of cellular enwrapment and suggests that reciprocal signaling between the DTC niche and the germ stem cells promotes enwrapment behavior and stem cell fate.
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Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology—the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin—and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function.

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ReviewScratching the niche that controls Caenorhabditis elegans germline stem cells

Abstract

Introduction

Section snippets

The distal tip cell provides a niche for germline stem cells

Molecular controls of niche specification and maintenance

Germ cell intrinsic controls of self-renewal

Conclusions and future directions

Acknowledgements

Dev Biol

Cell

Dev Biol

Cell

Curr Biol

Cell

Cell

Dev Biol

Dev Biol

Dev Biol

Int J Biochem Cell Biol

Dev Cell

Curr Biol

Curr Biol

Neuron

Curr Biol

Dev Biol

Trends Cell Biol

Dev Cell

Dev Cell

Dev Biol

Dev Biol

Biochem Biophys Res Commun

Cell

Trends Genet

Dev Biol

Dev Cell

Curr Biol

Neuron

Dev Cell

Dev Biol

Dev Biol

Dev Biol

J Lipid Res

The relationship between the spleen colony-forming cell and the haemopoietic stem cell

Blood Cells

Controls of germline stem cells, entry into meiosis, and the sperm/oocyte decision in Caenorhabditis elegans

Annu Rev Cell Dev Biol

Stem cells and their niche: an inseparable relationship

Development

Notch signaling in stem cell systems

Stem Cells

Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line

Mol Biol Cell

Control of the proliferation versus meiotic development decision in the C. elegans germline through regulation of GLD-1 protein accumulation

Development

Review
Scratching the niche that controls Caenorhabditis elegans germline stem cells