Controlling the size of organs and organisms

doi:10.1016/j.ceb.2005.09.008

Current Opinion in Cell Biology

Volume 17, Issue 6, December 2005, Pages 604-609

https://doi.org/10.1016/j.ceb.2005.09.008 Get rights and content

A key difference between yeast and metazoans is the need of the latter to regulate cell proliferation and growth to create organs (and organisms) of reproducible size and shape. Great progress has been made in understanding how growth, cell size and the cell cycle are controlled in metazoans. Recent work has shown that disruption of conserved components of the insulin and Tor kinase pathways can alter organ size, indicating that the normal functioning of these pathways is essential for organ size control. However, disruption of genes that regulate patterning and of genes that control cell adhesion and cell polarity has a much more dramatic effect on final organ size than does manipulation of the cell cycle or of basal growth control mechanisms. These data point to an ‘organ-size checkpoint’ that regulates cell division, cell growth and apoptosis. Recent data suggests that cell competition may play an important role in implementing the organ-size checkpoint.

Introduction

Experiments in yeast and in tissue culture cells have contributed enormously to our understanding of how cell growth and proliferation are controlled. Many of these insights have been validated in vivo when tested in genetic models such as mice, worms or flies. However, there are clearly additional mechanisms that function in developing tissues to constrain growth that cannot be studied in yeast or tissue culture models. Yeast and tissue culture cell lines will proliferate indefinitely, given sufficient nutrient conditions. In contrast, even given optimal conditions, flies and mice and elephants will attain reproducible sizes set by intrinsic genetic controls. It is still largely mysterious how this reproducible size control is achieved. We first briefly review basic, conserved mechanisms of growth control, and then discuss recent advances in understanding how growth and proliferation are controlled during development to generate organs of reproducible shape and size.

Section snippets

Basic growth control mechanisms

It has long been known that cells coordinate their growth and cell cycle, and will halt cell-cycle progression at specific checkpoints in G₁ or G₂ if the cell has not grown to a minimal size [1, 2]. The molecular basis of these cell size check-points is unclear, and it remains uncertain how a cell knows how big it is; it has been variously proposed that the cell measures mass, volume or translation rates. Cell growth does not depend on progression through the cell division cycle; mutations that

Coordinating growth with tissue morphogenesis

To understand how growth and proliferation are regulated in the context of a developing tissue, we will concentrate on one of the best-understood developing tissues, the Drosophila wing imaginal disc. The disc grows from 50 cells to 50 000 cells over a period of four days [12]. Growth rates are high at the beginning of development, and rapidly slow down as the tissue reaches its final size. Growth and patterning of the wing are dependent on the morphogens Wg and Dpp. Wg and Dpp are expressed in

Compartments and growth control

The expression of Dpp marks the border between the anterior and posterior compartments of the wing disc (Figure 1a). Extensive work has indicated that compartments are a fundamental unit of growth control. Compartments are cell-lineage-restricted regions of growth; a cell born in the anterior compartment will stay in that compartment, as will all of its daughters. If a cell has a growth advantage over its neighbors, it will overproliferate, outcompeting its neighbours, and populate the entire

The role of cell death in controlling organ size

Work mostly in vertebrates has shown that apoptosis is an important mechanism for keeping cells in the correct location. Cells in tissues rely on locally produced growth factors to continually provide anti-apoptotic signals. If a cell wanders away from its normal location, it no longer receives these anti-apoptotic signals and dies. This provides a powerful mechanism for blocking inappropriate growth and limiting tumour metastasis. Induction of apoptosis is also a powerful mechanism for

What is the organ size checkpoint?

It is clear that there is an intrinsic mechanism in all metazoans that enables an organ to ‘know’ its size and to regulate growth accordingly. If a human liver is surgically reduced, it will regenerate and grow to its proper size, and then cease growth [34]. If multiple fetal mouse thymus glands are transplanted into an adult mouse they will each grow normally until reaching the correct adult size, and then stop [35]. Similarly, if a larval wing disc is transplanted into an adult fly, it will

Cell adhesion, cell polarity and organ size control

Perturbations that enhance growth rates or that remove cell cycle inhibitors generally produce at most one extra round of cell division, or moderate cell size increases leading to increases in organism and organ size of up to 50%. Overexpression or mis-expression of patterning genes has a more dramatic effect, and can double or triple organ mass. However, the most dramatic effects on organ size are seen with mutations of genes involved in cell–cell adhesion, cell polarity and cell–cell junction

Perspectives

Clearly more questions have been raised than answered when it comes to understanding the ‘organ size checkpoint’. However, understanding such a checkpoint is crucial to our understanding of normal development. It may also have important implications for understanding cancer, since in cancer cells lose the normal brakes on proliferation and seem to ignore the normal ‘stop signals’. Intriguingly, loss of cell polarity is also a hallmark of advanced cancers, and accompanies unrestrained

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (48)

P. Jorgensen et al.
How cells coordinate growth and division
Curr Biol
(2004)
G.C. Johnston et al.
Coordination of growth with cell division in the yeast Saccharomyces cerevisiae
Exp Cell Res
(1977)
T.P. Neufeld et al.
Coordination of growth and cell division in the Drosophila wing
Cell
(1998)
J. Colombani et al.
A nutrient sensor mechanism controls Drosophila growth
Cell
(2003)
N. Arquier et al.
Drosophila Lk6 kinase controls phosphorylation of eukaryotic translation initiation factor 4E and promotes normal growth and development
Curr Biol
(2005)
J.H. Reiling et al.
Diet-dependent effects of the Drosophila Mnk1/Mnk2 homolog Lk6 on growth via eIF4E
Curr Biol
(2005)
J.M. Bateman et al.
Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila
Cell
(2004)
D. Nellen et al.
Direct and long-range action of a DPP morphogen gradient
Cell
(1996)
F.A. Spencer et al.
Decapentaplegic: a gene complex affecting morphogenesis in Drosophila melanogaster
Cell
(1982)
G. Struhl et al.
Organizing activity of wingless protein in Drosophila
Cell
(1993)

G. Morata et al.

Minutes: mutants of Drosophila autonomously affecting cell division rate

Dev Biol

(1975)

P. Simpson et al.

Differential mitotic rates and patterns of growth in compartments in the Drosophila wing

Dev Biol

(1981)

C. de la Cova et al.

Drosophila myc regulates organ size by inducing cell competition

Cell

(2004)

S.S. Grewal et al.

Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development

Nat Cell Biol

(2005)

V. French et al.

Pattern regulation in epimorphic fields

Science

(1976)

A.M. Brumby et al.

scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila

EMBO J

(2003)

P. Nurse

The genetic control of cell volume

K. Weigmann et al.

Cell cycle progression, growth and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase

Development

(1997)

S.J. Day et al.

Measuring dimensions: the regulation of size and shape

Development

(2000)

S. Leevers et al.

Growth regulation by insulin and TOR signaling in Drosophila

P.J. Bryant et al.

Intrinsic and extrinsic control of growth in developing organs

Q Rev Biol

(1984)

T. Lecuit et al.

Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing

Nature

(1996)

M. Zecca et al.

Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing

Development

(1995)

C. Martin-Castellanos et al.

A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing

Development

(2002)

Cited by (65)

Cell competition, cooperation, and cancer
2021, Neoplasia (United States)
Citation Excerpt :
In an attempt to define the biological perimeter of this phenomenon, a series of “hallmarks” have been proposed to characterize cell competition [26]. They include: (1) a context-dependency effect, i.e. a fitness gradient must exist for the winner vs. loser cell phenotype to emerge; (2) a mechanistic coupling between proliferation of winner and clearance of loser cells; (3) maintenance of overall tissue size, i.e. cell competition occurs under homeostatic control mechanisms; (4) importantly, the process is enforced within defined developmental compartments [26,27]. A relevant aspect that emerges from the above is that cell competition is enacted at a high hierarchical level, beyond that of single cells, allowing tissues and/or organisms to implement quality control strategies in order to maintain functional proficiency of their constituent cells.
Complex multicellular organisms require quantitative and qualitative assessments on each of their constitutive cell types to ensure coordinated and cooperative behavior towards overall functional proficiency. Cell competition represents one of the operating arms of such quality control mechanisms and relies on fitness comparison among individual cells. However, what is exactly included in the fitness equation for each cell type is still uncertain. Evidence will be discussed to suggest that the ability of the cell to integrate and collaborate within the organismal community represents an integral part of the best fitness phenotype. Thus, under normal conditions, cell competition will select against the emergence of altered cells with disruptive behavior towards tissue integrity and/or tissue pattern formation. On the other hand, the winner phenotype prevailing as a result of cell competition does not entail, by itself, any degree of growth autonomy. While cell competition per se should not be considered as a biological driving force towards the emergence of the neoplastic phenotype, it is possible that the molecular machinery involved in the winner/loser interaction could be hijacked by evolving cancer cell populations.
Coordination between Cell Motility and Cell Cycle Progression in Keratinocyte Sheets via Cell-Cell Adhesion and Rac1
2020, iScience
Citation Excerpt :
Collective behaviors of cells are essential for development, regeneration, and homeostasis of tissues, wherein cells migrate, grow, proliferate, differentiate, and even die in a collective manner (Leevers and McNeill, 2005; Lecuit and Le Goff, 2007; Friedl and Gilmour, 2009; Aman and Piotrowski, 2010; Garcia-Hughes et al., 2015).
Regulations of cell motility and proliferation are essential for epithelial development and homeostasis. However, it is not fully understood how these cellular activities are coordinated in epithelial collectives. In this study, we find that keratinocyte sheets exhibit time-dependent coordination of collective cell movement and cell cycle progression after seeding cells. Cell movement and cell cycle progression are coordinately promoted by Rac1 in the “early phase” (earlier than ∼30 h after seeding cells), which is not abrogated by increasing the initial cell density to a saturated level. The Rac1 activity is gradually attenuated in the “late phase” (later than ∼30 h after seeding cells), leading to arrests in cell motility and cell cycle. Intact adherens junctions are required for normal coordination between cell movement and cell cycle progression in both early and late phases. Our results unveil a novel basis for integrating motile and proliferative behaviors of epithelial collectives.
The Hippo Pathway: A Master Regulatory Network Important in Development and Dysregulated in Disease
2017, Current Topics in Developmental Biology
Citation Excerpt :
Originally, the Hippo homologs in mammalian systems were identified as stress response kinases Mst1 and Mst2 (also referred to as Krs1, Krs2 or Stk4 and Stk3) and were reported to play a role in responding to stress and in promoting apoptosis (Creasy & Chernoff, 1995a, 1995b; Kakeya et al., 1998; Taylor et al., 1996). Developing organs know when to stop growing at the appropriate size; in contexts of changes in proliferation or developmental stressors, they employ mechanisms to achieve but not exceed that predetermined size in what is sometimes called an “organ size checkpoint” (Leevers & McNeill, 2005). Mature organs then continue to engage homeostatic mechanisms to maintain that size in a mature organism.
The Hippo Pathway is a master regulatory network that regulates proliferation, cell growth, stemness, differentiation, and cell death. Coordination of these processes by the Hippo Pathway throughout development and in mature organisms in response to diverse external and internal cues plays a role in morphogenesis, in controlling organ size, and in maintaining organ homeostasis. Given the importance of these processes, the Hippo Pathway also plays an important role in organismal health and has been implicated in a variety of diseases including eye disease, cardiovascular disease, neurodegeneration, and cancer. This review will focus on Drosophila reports that identified the core components of the Hippo Pathway revealing specific downstream biological outputs of this complicated network. A brief description of mammalian reports will complement review of the Drosophila studies. This review will also survey upstream regulation of the core components with a focus on feedback mechanisms.
Involvement of receptor activator of nuclear factor-κB ligand (RANKL)-induced incomplete cytokinesis in the polyploidization of osteoclasts
2016, Journal of Biological Chemistry
Osteoclasts are specialized polyploid cells that resorb bone. Upon stimulation with receptor activator of nuclear factor-κB ligand (RANKL), myeloid precursors commit to becoming polyploid, largely via cell fusion. Polyploidization of osteoclasts is necessary for their bone-resorbing activity, but the mechanisms by which polyploidization is controlled remain to be determined. Here, we demonstrated that in addition to cell fusion, incomplete cytokinesis also plays a role in osteoclast polyploidization. In in vitro cultured osteoclasts derived from mice expressing the fluorescent ubiquitin-based cell cycle indicator (Fucci), RANKL induced polyploidy by incomplete cytokinesis as well as cell fusion. Polyploid cells generated by incomplete cytokinesis had the potential to subsequently undergo cell fusion. Nuclear polyploidy was also observed in osteoclasts in vivo, suggesting the involvement of incomplete cytokinesis in physiological polyploidization. Furthermore, RANKL-induced incomplete cytokinesis was reduced by inhibition of Akt, resulting in impaired multinucleated osteoclast formation. Taken together, these results reveal that RANKL-induced incomplete cytokinesis contributes to polyploidization of osteoclasts via Akt activation.
Insulin-induced cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner
2015, Cellular Signalling
Beyond its key role in the control of energy metabolism, insulin is also an important regulator of cell division and neoplasia. However, the molecular events involved in insulin-driven cell proliferation are not fully elucidated. Here, we show that the ubiquitin ligase Chfr, a checkpoint protein involved in G2/M transition, is a new effector involved in the control of insulin-induced cell proliferation. Chfr is identified as a partner of the molecular adapter Grb14, an inhibitor of insulin signalling. Using mammalian cell lines and the Xenopus oocyte as a model of G2/M transition, we demonstrate that Chfr potentiates the inhibitory effect of Grb14 on insulin-induced cell division. Insulin stimulates Chfr binding to the T220 residue of Grb14. Both Chfr binding site and Grb14 C-ter BPS-SH2 domain, mediating IR binding and inhibition, are required to prevent insulin-induced cell division. Targeted mutagenesis revealed that Chfr ligase activity and phosphorylation of its T39 residue, a target of Akt, are required to potentiate Grb14 inhibitory activity. In the presence of insulin, the binding of Chfr to Grb14 activates its ligase activity, leading to Aurora A and Polo-like kinase degradation and blocking cell division. Collectively, our results show that Chfr and Grb14 collaborate in a negative feedback loop controlling insulin-stimulated cell division.
Regulation of Jaw Length During Development, Disease, and Evolution
2015, Current Topics in Developmental Biology
Molecular and cellular mechanisms that control jaw length are becoming better understood. This is significant since the jaws are not only critical for species-specific adaptation and survival, but they are often affected by a variety of size-related anomalies including mandibular hypoplasia, retrognathia, asymmetry, and clefting. This chapter overviews how jaw length is established during the allocation, proliferation, differentiation, and growth of jaw precursor cells, which originate from neural crest mesenchyme (NCM). The focus is mainly on results from experiments transplanting NCM between quail and duck embryos. Quail have short jaws whereas those of duck are relatively long. Quail–duck chimeras reveal that the determinants of jaw length are NCM mediated throughout development and include species-specific differences in jaw progenitor number, differential regulation of various signaling pathways, and the autonomous activation of programs for skeletal matrix deposition and resorption. Such insights help make the goal of devising new therapies for birth defects, diseases, and injuries to the jaw skeleton seem ever more likely.

View all citing articles on Scopus

View full text

Controlling the size of organs and organisms

Introduction

Section snippets

Basic growth control mechanisms

Coordinating growth with tissue morphogenesis

Compartments and growth control

The role of cell death in controlling organ size

What is the organ size checkpoint?

Cell adhesion, cell polarity and organ size control

Perspectives

References and recommended reading

Curr Biol

Exp Cell Res

Cell

Cell

Curr Biol

Curr Biol

Cell

Cell

Cell

Cell

Dev Biol

Dev Biol

Cell

Nat Cell Biol

Science

EMBO J

The genetic control of cell volume

Cell cycle progression, growth and patterning in imaginal discs despite inhibition of cell division after inactivation of Drosophila Cdc2 kinase

Development

Measuring dimensions: the regulation of size and shape

Development

Growth regulation by insulin and TOR signaling in Drosophila

Intrinsic and extrinsic control of growth in developing organs

Q Rev Biol

Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing

Nature

Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing

Development

A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing

Development