Controlling the size of organs and organisms

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.     

Cell number counts - The fw2.2 and CNR genes and implications for controlling plant fruit and organ size

Two key determinants of plant and organ size are cell number and cell size, and altering either one may affect the plant organ size, but cell number control often plays a predominant role in natural populations. Domesticated crops usually have larger fruit and harvested organ sizes than wild progenitors. Crop yields have increased significantly by breeding, often via heterosis, which is associated with increased plant and organ size primarily achieved by cell number increases. A small class of genes is now known that control plant and organ sizes though cell number or cell size. The fw2.2 gene was found to control a major QTL for tomato fruit size by negatively affecting cell numbers. Orthologs to these fw2.2 genes underlie QTLs for fruit sizes in other species, and their expression can be negatively correlated with increased cell number. In maize decreased or increased expression of the fw2.2 ortholog ZmCNR1, increases or decreases cell number, respectively, thereby affecting maize organ size throughout the plant and thus also whole plant size. Therefore, these genes should now be considered as more general regulators of plant cell number and organ size. The exact molecular function of these transmembrane domain proteins remains unknown, as does any clear relationship to the cell cycle. Because these genes control organ sizes in diverse plants and important crop species, and because they can affect whole plant size, interest arose into how effects of such genes could parallel agronomic crop improvements, in particular that by heterosis, as it also affects cell number. In joining these subjects here in discussion we speculate on how single gene cell number regulation and heterosis may cooperate in crop improvement.     

"Big it up": endoreduplication and cell-size control in plants

Cells undergoing endoreduplication replicate chromosomal DNA without intervening mitoses. The resulting larger, higher-ploidy nucleus is often associated with an increase in cell size, but the molecular basis for this correlation remains poorly understood. Recent advances in characterising various mutants and transgenic plants are beginning to unravel how this unique type of cell cycling is regulated and how it contributes to cell-size control. Both cell growth (i.e. increase in cytoplasmic macromolecular mass) and cell expansion (i.e. increase in cell volume through vacuolation) contribute independently to increases in cell size in plants. A total organ-size checkpoint may also help to coordinate cell size and cell number within an organ, and can contribute to final cell-size determination in plants.     

控制植物器官大小的分子机理

植物器官大小是植物形态的一个重要特征并受严格的遗传调控。器官大小与两个不同的过程有关：细胞扩张和细胞分裂。分子遗传分析已经鉴定了许多基因,这些基因通过作用于其中一个或两个过程来影响器官的最终大小。某种植物个体间器官大小的差异是由控制该器官特征的基因表达水平变化引起的,通过拟南芥的遗传分析显示这些基因是如何受控制或被修饰的。以上这些资料阐明了植物如何确定继续或停止生长,同时也提供了改变植物积累生物量的方法。     

Systematic identification of cell size regulators in budding yeast

Cell size is determined by a complex interplay between growth and division, involving multiple cellular pathways. To identify systematically processes affecting size control in G1 in budding yeast, we imaged and analyzed the cell cycle of millions of individual cells representing 591 mutants implicated in size control. Quantitative metric distinguished mutants affecting the mechanism of size control from the majority of mutants that have a perturbed size due to indirect effects modulating cell growth. Overall, we identified 17 negative and dozens positive size control regulators, with the negative regulators forming a small network centered on elements of mitotic exit network. Some elements of the translation machinery affected size control with a notable distinction between the deletions of parts of small and large ribosomal subunit: parts of small ribosomal subunit tended to regulate size control, while parts of the large subunit affected cell growth. Analysis of small cells revealed additional size control mechanism that functions in G2/M, complementing the primary size control in G1. Our study provides new insights about size control mechanisms in budding yeast.     

Molecular mechanism of size control in development and human diseases

How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.     

The Arabidopsis auxin-inducible gene ARGOS controls lateral organ size

During plant development, the final size of an organ is regulated and determined by various developmental signals; however, the molecular mechanisms by which these signals are transduced and the mediators involved are largely unknown. Here, we show that ARGOS, a novel Arabidopsis gene that is highly induced by auxin, is involved in organ size control. Transgenic plants expressing sense or antisense ARGOS cDNA display enlarged or reduced aerial organs, respectively. The alteration in organ size is attributable mainly to changes in cell number and the duration of organ growth. Ectopic expression of ARGOS prolongs the expression of AINTEGUMENTA (ANT) and CycD3;1 as well as the neoplastic activity of leaf cells. Moreover, organ enlargement in plants overexpressing ARGOS can be blocked by the loss of function of ANT, implying that ARGOS functions upstream of ANT to affect the meristematic competence of organ cells. The induction of ARGOS by auxin is attenuated or abolished in auxin-resistant1 (axr1), and overexpression of ARGOS partially restores axr1 organ development. These results suggest that ARGOS may transduce auxin signals downstream of AXR1 to regulate cell proliferation and organ growth through ANT during organogenesis.     

Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells

Following DNA damage, human cells undergo arrests in the G(1) and G(2) phases of the cell cycle and a simultaneous arrest in cell size. We previously demonstrated that the cell size arrest can be uncoupled from the cell cycle arrest by mutational inactivation of the PTEN tumor suppressor gene. Here we show that the cell size checkpoint is inducible by DNA-damaging chemotherapeutic agents as well as by ionizing radiation and is effectively regulated by PTEN but not by its oncogenic counterpart, PIK3CA. Mutational analysis of PTEN and pharmacological inhibition of Akt revealed that modulation of Akt phosphorylation is unnecessary for cell size checkpoint control. To discover putative PTEN regulators and/or effectors involved in size checkpoint control, we employed a novel endogenous epitope tagging (EET) approach, which revealed that endogenous PTEN interacts at the membrane with an actin-remodeling complex that includes actin, gelsolin, and EPLIN. Pharmacological inhibition of actin remodeling in PTEN(+/+) cells recapitulated the lack of size checkpoint control seen in PTEN(-/-) cells. Taken together, these results provide further support for the existence of a DNA damage-inducible size checkpoint that is regulated by a major tumor suppressor, and they provide a novel Akt-independent mechanism by which PTEN controls cell size.     

The control of body size in insects

Control mechanisms that regulate body size and tissue size have been sought at both the cellular and organismal level. Cell-level studies have revealed much about the control of cell growth and cell division, and how these processes are regulated by nutrition. Insulin signaling is the key mediator between nutrition and the growth of internal organs, such as imaginal disks, and is required for the normal proportional growth of the body and its various parts. The insulin-related peptides of insects do not appear to control growth by themselves, but act in conjunction with other hormones and signaling molecules, such as ecdysone and IDGFs. Size regulation cannot be understood solely on the basis of the mechanisms that control cell size and cell number. Size regulation requires mechanisms that gather information on a scale appropriate to the tissue or organ being regulated. A new model mechanism, using autocrine signaling, is outlined by which tissue and organ size regulation can be achieved. Body size regulation likewise requires a mechanism that integrates information at an appropriate scale. In insects, this mechanism operates by controlling the secretion of ecdysone, which is the signal that terminates the growth phase of development. The mechanisms for size assessment and the pathways by which they trigger ecdysone secretion are diverse and can be complex. The ways in which these higher-level regulatory mechanisms interact with cell- and molecular- level mechanisms are beginning to be elucidated.     

拟南芥YUAN1基因调控器官形状和大小

器官形状和大小的控制是一个基本的发育生物学过程, 受细胞分裂和细胞扩展的影响。到目前为止, 人们对植物器官形状和大小的调控机制知之甚少。本实验室前期研究发现了一个种子和器官大小的调控基因DA1, 其编码一个泛素受体。在拟南芥(Arabidopsis thaliana)中, DA1通过抑制细胞的分裂来限制种子和器官的大小。本研究通过激活标签的方法在da1-1突变体背景下筛选到一个叶子形状发生改变的半显性突变体(yuan1-1D)。yuan1-1D形成短而圆的叶片和短的叶柄, 细胞学分析显示, 叶片和叶柄变短的主要原因是细胞的长向扩展降低导致的。YUAN1编码一个含有PHD锌指结构域的蛋白。GFP-YUAN1融合蛋白定位在细胞核内。过量表达YUAN1基因导致叶片和叶柄变短。遗传学分析显示, YUAN1和DA1、ROT3以及ROT4在控制叶片形状和大小方面作用于不同的遗传途径中。因此, 本研究鉴定了一个新的控制器官形状和大小的基因YUAN1, 为阐明植物器官形状和大小调控的分子机制提供了重要线索。     

Leaf size control: complex coordination of cell division and expansion

Size control of multicellular organisms poses a longstanding biological question that has always fascinated scientists. Currently the question is far from being resolved because of the complexity of and interconnection between cell division and cell expansion, two different events necessary to form a mature organ. Because of the importance of plants for food and renewable energy sources, dissecting the genetic networks underlying plant growth and organ size is becoming a high priority in plant science worldwide. Here, we review the current understanding of the cellular and molecular mechanisms that govern leaf organ size and discuss future prospects on research aiming at understanding organ size regulation.     

Loss of growth homeostasis by genetic decoupling of cell division from biomass growth: implication for size control mechanisms

Growing cells adjust their division time with biomass accumulation to maintain growth homeostasis. Size control mechanisms, such as the size checkpoint, provide an inherent coupling of growth and division by gating certain cell cycle transitions based on cell size. We describe genetic manipulations that decouple cell division from cell size, leading to the loss of growth homeostasis, with cells becoming progressively smaller or progressively larger until arresting. This was achieved by modulating glucose influx independently of external glucose. Division rate followed glucose influx, while volume growth was largely defined by external glucose. Therefore, the coordination of size and division observed in wild‐type cells reflects tuning of two parallel processes, which is only refined by an inherent feedback‐dependent coupling. We present a class of size control models explaining the observed breakdowns of growth homeostasis.     

Making bigger plants: key regulators of final organ size

Organ growth in plants is controlled by both genetic factors and environmental inputs. Recent progress has been made in identifying genetic determinants of final organ size and in characterizing a pathway that may link organ growth with environmental conditions. Some identified growth regulatory factors act downstream of plant hormones, while others appear to be components of novel signaling pathways. Additional characterization of these proteins is needed before we can understand how growth-promoting and growth-restricting inputs are integrated to coordinate growth within a developing organ. Some parallels in the mechanisms used by plants and animals to regulate organ size are suggested by the identification of KLUH, a noncell-autonomous regulator of organ growth, and by similarities in the target of rapamycin (TOR)-signaling pathway.     

Mechanisms of size control

The study of organ size control is a discipline of developmental biology that is largely unexplored. Although the size of an organ or organism depends largely on cell numbers and cell size, studies have found that the simple deregulation of cell proliferation or cell growth does not necessarily lead to changes in organ size. Recent genetic screens in Drosophila suggest that mutations that do affect organ size can be classified into three broad categories on the basis of their underlying effects: patterning, proliferation, and growth. Overall, experimental data suggest that organ size might be regulated by a 'total mass checkpoint' mechanism which functions to link the regulation of cell size and cell proliferation. The mechanisms of organ size control could also be critical targets for evolutionary events or disease processes such as tumorigenesis.