Sci. Aging Knowl. Environ., 24 September 2003
Vol. 2003, Issue 38, p. re7
[DOI: 10.1126/sageke.2003.38.re7]

REVIEWS

Mitotic and Postmitotic Senescence in Plants

Susheng Gan

The author is at the Cornell Genomics Initiative and Department of Horticulture, G51 Emerson Hall, Cornell University, Ithaca, NY 14853-5904, USA. E-mail: sg288{at}cornell.edu

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/38/re7

Key Words: Arabidopsis • genomics • leaf • meristem • senescence • telomere

Abstract: Plants exhibit both mitotic and postmitotic senescence. Mitotic senescence, also known as proliferative senescence, occurs when germline-like meristem cells lose their ability to undergo mitotic cell division. Unlike replicative senescence in yeast and human cells in culture, mitotic senescence in plants is not controlled by telomere shortening. Postmitotic senescence, an active degenerative process, occurs in organs such as leaves and floral petals. Substantial progress has been made toward understanding the molecular mechanisms of postmitotic senescence (especially leaf senescence). Leaf senescence is a form of programmed cell death that can be regulated by an array of endogenous factors and environmental cues. Gene expression is required in order for leaf cells to die. In Arabidopsis thaliana, up to 2500 genes (including more than 130 that encode transcription factors) are transcribed during leaf senescence. Mutant analysis and functional genomics approaches have revealed important roles for several of these genes in leaf senescence. In addition to summarizing our current understanding of senescence in plants at the molecular level, this Review compares mechanisms of senescence in yeast and animal systems.

Introduction Back to Top

Plants, like many other organisms, exhibit various life history patterns and possess a broad spectrum of longevity, ranging from a few weeks to several hundred years. It has long been speculated that the life pattern and life span of a given species are determined genetically. Although much research concerning the morphological, physiological, and biochemical changes associated with life attrition has been done, the controlling mechanisms of life span remain elusive. Recent molecular genetic analyses of plant senescence, especially in the model plant Arabidopsis thaliana, have shed some light on this fundamental biological question. This Review summarizes our current understanding of both mitotic and postmitotic senescence in plants at the molecular level, and, where appropriate, comparisons with mechanisms of senescence in yeast and animal systems are made.

Plants Exhibit Both Mitotic and Postmitotic Senescence Back to Top

A cell's life history consists of mitotic and postmitotic processes (Fig. 1). A cell may undergo a certain number of rounds of mitosis to produce daughter cells. The stage when mitotic cell division ends is referred to as mitotic senescence. In the literature concerning yeast and mammalian cells in culture, this type of senescence is referred to as replicative senescence, replicative aging, or replicative life span (1, 2). In contrast, postmitotic senescence is the active degenerative process leading to the death of a cell that no longer undergoes mitotic division. Plants exhibit both types of senescence. An example of mitotic senescence in plants is the arrest of cell division in the apical meristem; the meristem consists of nondifferentiated germline-like cells that can divide many times to produce cells that will then differentiate and form new organs, such as leaves and flowers. In the plant literature, the arrest of cells in the apical meristem is also called proliferative senescence (3). Postmitotic senescence occurs in some plant organs such as the leaf and the floral petal. Once formed, cells in these organs experience cell expansion but rarely undergo cell division; thus, their ultimate senescence is not the result of an inability to divide. This type of senescence, which predominantly involves somatic tissues, is similar to that which occurs in such animal model systems as Drosophila and Caenorhabditis elegans, where the adult body, with the exception of the germline, is postmitotic.



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Fig. 1. Illustration of a cell's life history. The cell undergoes two types of senescence: mitotic and postmitotic. When the cell loses the ability to divide, the process is called mitotic, replicative, or proliferative senescence. When a cell that can no longer divide undergoes an active degenerative process, the process is called postmitotic senescence.

 

Mitotic/Replicative/Proliferative Senescence in Plants Back to Top

The initiation of the generation of all above-ground postembyonic organs in plants takes place in the shoot apical meristem (4) and is regulated by the homeodomain/leucine zipper transcription factor REVOLUTA (5). REVOLUTA also controls the relative growth of the apical meristem in Arabidopsis (6). In contrast to their initiation and growth, the arrest of apical meristems might be regulated in part by the FIREWORKS (FIW) gene product, because homozygous mutant fiw/fiw plants displayed cell cycle arrest in the inflorescence (flower-bearing stem axis) meristem 7 days earlier than did wild-type Arabidopsis plants (7). Otherwise, the mutant plants developed normally, produced normal flowers, and set fully matured siliques, which are the seed vessels or pods of plants. The FIW gene has not yet been cloned, and the nature and mode of its regulation need to be deciphered.

Reproductive development appears to play an important role in regulating proliferative senescence in plants, which is especially true in many monocarpic plants. Monocarpic plants are plant species that have only a single phase of reproductive growth in their life cycles; after flowering and setting seeds or fruits, the whole plant senesces. Many annuals and biennials (for example, Arabidopsis and wheat), and even some perennials (for example, bamboo) are monocarpic plants. Hensel et al. (3) found that the meristems of all inflorescence branches in the wild-type Arabidopsis ecotype Landsberg erecta (Ler) ceased to produce flowers coordinately, but such a coordinated proliferative arrest did not occur in wild-type Ler plants with their fruits surgically removed. Similarly, meristem arrest was not observed in a male-sterile Ler line that never produces seeds. Therefore, it is likely that a specific communication system exists between inflorescence meristems and developing seeds (3). However, the nature of such a communication system remains to be determined.

Human cells in culture have a molecular clock that counts the number of cell divisions (1). The nature of the molecular clock appears to be the shortening of telomeres: the specialized structures made up of repetitive DNA and associated proteins that are found at the ends of chromosomes (see "More Than a Sum of Our Cells"). Telomere length in human fibroblasts decreases as a function of the number of cell divisions in vitro and possibly in vivo (8); conversely, countering the telomere-shortening process by expressing the catalytic subunit of telomerase (the enzyme that maintains telomere length) significantly prolongs the replicative life span of human cells in vitro (9). In contrast, telomere shortening in plants (especially in the meristems) is trivial because the meristem cells possess telomerase activity (10), and the telomere length remains constant throughout the life cycle of, for example, Arabidopsis and the herbaceous plant Silene latifolia (11, 12). An exception has been reported in barley, where a significant reduction (50 kb) in telomere length occurs during embryogenesis (13). However, it should be noted that, in plants, mitotic cell division occurs predominantly in the meristems, and no detailed analysis of changes in telomere length in young versus senescent meristems has been reported, perhaps because of inherent technical difficulties in collecting enough meristems for analysis. The cell culture system has been employed for studies of telomere length, although the mitotic senescence process in cultured plant cells has not been well characterized. In contrast to the situation in cultured human cells, telomere length in cultured plant cells increases rather than decreases during prolonged culture (12, 13). It is puzzling that Arabidopsis telomerase-null mutant plants display a slow loss of telomeric DNA [~500 base pairs (bp) per generation, which is 10 times slower than that observed in telomerase-deficient mice] (11), and both the plants themselves and the cells in the shoot meristems exhibit an extended life span. The meristems are enlarged and disorganized and sometimes form a tumorlike mass (14). It is therefore unlikely that telomere shortening plays an important role in controlling proliferative senescence in plants. The molecular mechanisms underlying mitotic senescence in plants remain to be deciphered.

Postmitotic Senescence in Plants Back to Top

Although xylogenesis (the process by which certain cells die to form vascular elements that conduct water and some nutrients), the hypersensitive response (during which infected cells die to prevent pathogens from spreading in resistant plants), and several other processes involving plant cell death are sometimes called senescence (15) and are postmitotic in nature, in this Review only leaf senescence-related research will be discussed.

Leaf Senescence Syndrome Back to Top

Leaf development encompasses the progression from formation of the leaf primordium (the outgrowth from the apical meristem that develops into a leaf) to expansion, maturation, and attrition of this organ. The final phase from maturation to attrition in the leaf life history is referred to as leaf senescence. Leaf senescence also occurs in harvested or detached leaves. Leaf yellowing is the visible sign of leaf senescence and results from the preferential degradation of the green pigment chlorophyll but not the carotenoids, which are yellow-red pigments that also function in photosynthesis. In some plant species, the synthesis of anthocyanins and other pigments accompanies the senescence process and contributes to the various colors in autumn leaves. Because of the loss of chlorophyll, the photosynthetic capacity of a leaf decreases sharply during senescence. Anabolism of carbohydrates, amino acids, and other components is replaced by catabolism of macromolecules such as proteins, lipids, and nucleic acids (DNA and RNA), and the released nutrients are translocated to actively growing regions of the plant such as new buds, young leaves, and developing fruits and seeds, or are stored in trunks for the next growing season (16). The nutrient recycling process is thus considered to be an example of evolutionary fitness, in that it improves the chances of survival and reproduction. The massive operation of catabolism and nutrient mining leads ultimately to cell death.

Subcellular Changes During Leaf Senescence Back to Top

Although the massive degradation that occurs in a cell during senescence appears to be a chaotic process, the cell actually undergoes highly ordered structural changes. The chloroplast generally disintegrates first, and the nucleus breaks down relatively late in the process. The most detailed microscopic analysis of this process has been done using the rice coleoptile: the first leaf that forms a protective sheath around the region of the embryonic plant that will form the shoot. All mesophyll cells (the green cells in a leaf) in the rice coleoptile share the following sequential events during senescence: (i) degradation of chloroplast DNA; (ii) a decrease in the size of chloroplasts, degradation of the chloroplast inner membranes and of ribulose-1,5-bisphosphate carboxylase/oxygenase (a chloroplast-targeted photosynthetic enzyme) and simultaneous condensation of the nucleus; (iii) disorganization of the nucleus; and (iv) distortion of the cell wall and complete loss of cellular components (17). The chloroplast is the organelle that contains up to 70% of the proteins in a mesophyll cell. Thus, it makes sense that the chloroplast is dismantled first while other cellular constituents, such as the nucleus, remain intact to accomplish the nutrient recycling process (see below) (18).

Induction/Promotion of Leaf Senescence Back to Top

The onset of leaf senescence is controlled by a complement of external and internal factors. Many environmental stressors and biological insults such as extreme temperature, drought, nutrient deficiency, insufficient light/shadow/darkness, and pathogen infection can induce senescence (19). Internal factors that influence senescence include age, concentrations of plant hormones/growth regulators, and developmental processes such as reproductive growth.

Age. In a natural setting, a plant inevitably encounters adverse and stressful environments that often induce leaf senescence. In the absence of external stressors, leaf senescence may occur in an age-dependent manner in many species (20-22), which is especially true in Arabidopsis. Individual leaves from wild-type Arabidopsis plants and various mutants in which the reproductive growth is either delayed (late-flowering mutants) or impaired (male or female sterile mutants) have an identical longevity (20-22). How age initiates leaf senescence is not well understood. It has been speculated that a decline in the activity of photosynthesis with age is a possible mechanism (20). However, the Arabidopsis mutant ore4 (which contains a lesion in a plastid ribosomal small subunit protein) displays reduced photosynthetic activity and delayed, rather than accelerated, age-dependent leaf senescence (23). Expression of the Arabidopsis gene SAG12 (which encodes a cysteine protease) occurs specifically during senescence and appears to be regulated by developmental age but not by other environmental or endogenous factors (24, 25). Analysis of the regulatory mechanism that controls SAG12 expression might provide insight into the age-dependent mechanisms of leaf senescence.

Sugars. In plants, sugar status modulates and coordinates internal regulators and environmental cues that govern growth and development (26). In general, scientists agree that sugar concentrations regulate leaf senescence, but the effect of high versus low sugar concentrations on leaf senescence has been controversial. Leaves are the primary site where sugars are produced through photosynthesis. Photosynthetic activity declines sharply during leaf senescence; this activity is also low in leaves that live in shadow or complete darkness, and both of these conditions induce leaf senescence. These findings led to the proposal that a low concentration of sugars induces leaf senescence (20, 27). Two lines of evidence, however, suggest that a high concentration of sugars triggers the leaf senescence program. First, sugar levels are higher in senescing as compared to nonsenescing leaves of Arabidopsis and tobacco plants (28, 29). Second, when yeast invertase (an enzyme that catalyzes the breakdown of sucrose into fructose and glucose) is expressed in the extracellular spaces of leaves from Arabidopsis, tobacco, and tomato plants, sugars accumulate and the leaves undergo premature senescence (30, 31).

Sugar concentrations are believed to be sensed by, for example, hexokinases (HXKs), which catalyze the first reaction of glycolysis. When an HXK is overexpressed in tomato plants, the leaves are precociously senescent, as if they contained an increased concentration of sugars (although the actual sugar concentration is lower than that of control plants). In contrast, Arabidopsis hxk1 knockout/null mutant plants display a delayed leaf senescence phenotype in the presence of high concentrations of sugars that are obtained by either exogenous sugar application or by increasing light intensity (thus increasing photosynthetic sugar production) (32). In mammals, glucose sensing by HXKs is somehow coupled with glucose metabolism: A high concentration of glucose results in increased glucose metabolism and a resultant increase in the concentration of adenosine triphosphate (ATP). This then leads to the activation of K+ channels, consequent alteration of the membrane potential, and ultimately insulin secretion by the pancreas beta-islet cells to regulate sugar metabolic rate. In contrast, sugar sensing in plants is independent of the catalytic activity of HXKs, as shown by the finding that mutant forms of HXK1 (in which the ATP-binding site or catalytic site has been abolished by site-directed mutagenesis) restore the hxk1 null line's ability to sense sugars (32). The decoupling of sugar sensing and metabolism clearly indicates that leaf senescence triggered by accumulating sugars most likely involves mechanisms other than enhanced sugar metabolism and calorie production. Metabolic energy has been associated with life span in many organisms; specifically, calorie restriction has been shown to extend life span in organisms ranging from yeast to mammals (including mice, rats, and possibly primates) (see "Monkey in the Middle"). Mutation of the C. elegans daf-2 gene, which encodes an insulin receptor-like protein, reduces metabolism and increases life span considerably (33) (see Johnson Subfield History).

Ethylene. Ethylene is a gaseous plant hormone that is involved in many aspects of plant growth and development, including leaf senescence. When ethylene biosynthesis is suppressed by antisense technology, leaf senescence in transgenic tomato plants is delayed (34). Leaf senescence is also delayed in Arabidopsis mutants that are deficient in ethylene perception and signal transduction [for example, plants carrying the etr1-1 (35, 36) and ein2/ora3 mutations] (37). However, leaves of transgenic Arabidopsis and tomato plants that constitutively overproduce ethylene do not exhibit precocious senescence, suggesting that ethylene alone is not sufficient to initiate leaf senescence. It has been postulated that age-dependent factors are required for ethylene-regulated leaf senescence [reviewed in (19)].

Jasmonic acid. Methyl jasmonate (MeJA), a major component of fragrant oils, and its precursor jasmonic acid (JA) were first shown to promote senescence in detached oat leaves (38) and were subsequently shown to play pervasive roles in several other aspects of plant development (39). A recent study showed that exogenous application of JA at a physiological concentration of 30 µM causes premature senescence in attached and detached leaves in wild-type Arabidopsis, but fails to induce precocious senescence of the JA-insensitive coi1 mutant, suggesting that the JA signaling pathway is required for JA to promote leaf senescence (40). Genes involved in JA biosynthesis are differentially up-regulated during leaf senescence, and the JA concentrations in senescing leaves are four times higher than those in nonsenescing leaves (40). JA-induced leaf yellowing is indeed an active senescence process, as shown by the finding that several genes that are specifically up-regulated during leaf senescence (so-called senescence-associated genes or SAGs) are expressed in the yellowing leaves (19). Although a precocious leaf senescence phenotype was not reported in transgenic potato plants that overproduce JA, this result might not necessarily contradict the proposed role of JA in senescence, because JA-inducible molecular markers were not induced in these plants (41). It is likely that JA is sequestered in this system so that it can not exert its biological effect (40). However, several Arabidopsis mutants that are deficient in JA production or JA signal transduction do not exhibit a delayed leaf senescence phenotype (40), which challenges the idea that JA plays a role in senescence. It is possible that other factors might induce leaf senescence in the absence of JA.

Salicylic acid. Salicylic acid (SA) is a phenolic compound produced by almost all plant species (see "Older and Stronger"). Its concentration varies from species to species and from tissue to tissue. The bark and leaves of the willow tree that were used for curing aches and fevers by Native Americans and ancient Greeks contain a relatively high concentration of acetylsalicylic acid (aspirin), a derivative of SA. Both SA and its derivative are active ingredients in many medications today. In humans, application of SA can cause aged skin cells to peel and can slow shedding of hair follicle cells to prevent acne formation. In plants, SA is a signal molecule involved in plant defense against pathogens that also plays a role in senescence. Although it has long been observed that a tablet of aspirin dissolved in water will increase the life of cut flowers, SA treatment induces premature leaf senescence. The concentrations of endogenous SA are four times higher in senescing leaves than in nonsenescing leaves (42). Arabidopsis plants have been generated that produce dramatically reduced quantities of SA as compared to the wild type, as a result of overexpression of a SA-degradating enzyme encoded by NahG. These plants, as well as Arabidopsis mutants defective in SA signaling (such as npr1 and pad4), display retarded leaf senescence and altered expression of some SAGs (42). These observations all indicate that SA promotes leaf senescence.

Brassinosteroids. This class of plant steroid hormones plays an essential role in diverse developmental programs, including leaf senescence (43). Two lines of evidence suggest a leaf senescence-promoting role for brassinosteroids (BRs). First, external application of 24-epi-brassinolide (eBR) induces senescence in mung bean leaves (44), cucumber cotyledons (45), and tomato fruits (46). Second, several Arabidopsis mutants that are deficient in either BR biosynthesis (for example, det2) or in the BR signaling pathway (for example, bri1) display a delayed leaf senescence phenotype [in addition to other characteristic changes; reviewed in (47)]. A mutation in a second gene that suppresses the bri1 phenotype has been identified. Plants that contain this mutation exhibit accelerated leaf senescence (48). It is believed that reactive oxygen species (ROS) might mediate BR-induced senescence, because after BR treatment in cucumber, the concentration of malondialdehyde (a compound produced as a consequence of oxidative stress) increases markedly and the activities of the antioxidant enzymes superoxide dismutase (SOD1) and catalase (CAT) are inhibited (44, 49) (see "The Two Faces of Oxygen"). eBR also induces the expression of a subset of potential SAGs in Arabidopsis (50). High concentrations of malondialdehyde have also been shown to be associated with accelerated senescence in, for example, senility-prone strains of male mice (51).

Abscisic acid. Abscisic acid (ABA) is a plant hormone formed from three isoprene units. It was so named because this hormone was originally thought to promote abscission (leaf, flower, or fruit shedding). Early studies showed that external application of ABA promotes senescence in detached leaves, but this effect is much less dramatic in in planta leaves (19). Environmental stress conditions such as drought, high salt concentrations, and low temperatures often induce leaf senescence, and concentrations of ABA in leaves increase when plants experience these conditions. Genetic studies show that various Arabidopsis mutants defective in either ABA biosynthesis or signaling display altered leaf senescence phenotypes, further suggesting a role for ABA in leaf senescence (19).

Inhibition of Leaf Senescence Back to Top

In contrast to the inducers/promotors discussed above, two categories of plant growth regulators--the cytokinins and the polyamines--are antagonists of leaf senescence.

Cytokinins. This class of plant hormones includes such adenine derivatives as kinetin, isopentenyl adenine, and zeatins. Kinetin was first discovered by Miller et al. (52) as a factor that promotes cell division in plant cells and tissue culture. Intriguingly, kinetin has also been shown to delay mitotic senescence in human cells in culture and to prolong the life span of fruit flies (53). Cytokinins have been implicated in almost all stages of plant growth and development, including postmitotic leaf senescence. Three approaches have been employed to investigate and support the inhibitory role of cytokinins in leaf senescence: (i) external application of cytokinins, (ii) measurement of endogenous cytokinin levels before and during senescence, and (iii) manipulation of endogenous cytokinin production in transgenic plants (54). For example, the leaf senescence-specific SAG12 promoter from Arabidopsis has been used to direct the expression of the gene that encodes isopentenyl transferase (IPT). IPT catalyses the first and rate-limiting step in the biosynthesis of cytokinins. When senescence begins in a leaf cell, the SAG12 promoter is activated to direct IPT gene expression, resulting in the biosynthesis of cytokinins. The increase in endogenous cytokinins in turn inhibits senescence. Because senescence is inhibited, the senescence-specific promoter becomes attenuated or inactivated, which prevents the overproduction of cytokinins. This forms an autoregulatory senescence inhibition system (Fig. 2A). Tobacco plants harboring this system display a significantly delayed leaf senescence phenotype (Fig. 2, B and C) (55). The longevity of the whole plant is also extended (Fig. 2B). A similar phenotype has been observed in other transgenic plants such as lettuce (56), bok choy (57), and broccoli (58). Overexpression of components of the cytokinin signal transduction pathway also delays leaf senescence in Arabidopsis (59), a result that further confirms the inhibitory role of cytokinins in leaf senescence.



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Fig. 2. Extension of life span by autoregulated production of cytokinins. (A) The senescence-specific (SS) promoter of SAG12 is used to direct expression of IPT, a gene encoding the cytokinin-synthesizing enzyme isopentenyl transferase. The onset of leaf senescence activates this promoter to direct the production of cytokinins. Cytokinins in turn inhibit senescence via mechanisms that are unknown. Once senescence is inhibited, the SS promoter is no longer activated, which prevents overproduction of cytokinins. When the level of cytokinins drops as a result of catabolism and the leaf cells start senescing, the SS promoter is activated to produce more cytokinins to inhibit senescence again. (B) A transgenic tobacco plant (left) containing the autoregulatory senescence inhibition system displays significantly delayed leaf senescence as compared with that of an age-matched wild-type plant (right). The transgenic plant still produces flowers, whereas the wild-type meristem has arrested. (C) A fully expanded, nonsenescing wild-type leaf (right) starts senescing 10 days after detachment; in contrast, the leaf of the transgenic plant (left) remains green until 40 days after detachment (55).

 
Polyamines. Polyamines (PAs), including putrescine, spermidine, and spermine, are ubiquitous cellular components that play important roles in cell proliferation, cell growth, and the synthesis of proteins and nucleic acids in a variety of living organisms, including yeasts, plants, and animals (60). In plants, PA concentrations are high in actively dividing cells but low in cells that do not grow and divide (61), suggesting that PAs might have a role in preventing mitotic senescence in plants (62). The idea that PAs play a role in preventing postmitotic senescence in plants is well supported by the fact that exogenous application of PAs can retard leaf senescence by preventing chlorophyll loss and membrane peroxidation and by inhibiting ribonuclease and protease activities in many plant species and experimental systems (63). A few counterexamples in which this effect does not take place have been observed, however (63).

S-adenosylmethionine is the common substrate for the biosynthesis of PAs and ethylene in plants. When ethylene production is blocked by antisense technology in transgenic tobacco plants, S-adenosylmethionine is channeled to the PA biosynthesis pathway, PA concentrations are substantially elevated, and stress-induced leaf senescence is retarded (64). However, as discussed above, ethylene promotes leaf senescence, so blocking ethylene biosynthesis might contribute at least in part to the delayed leaf senescence phenotype observed in these transgenic tobacco plants.

Genetic Regulation of Leaf Senescence Back to Top

Leaf senescence is under direct nuclear control. Like many other developmental processes, leaf senescence is a genetically controlled process rather than a passive degenerative course. One experiment that demonstrates this principle was performed using leaves from Elodea (a water weed). When these leaves were placed in a hypertonic solution, the mesophyll cells suddenly lost so much water that their plasma membranes pulled away from their cell walls (a process called plasmolysis). In some cells, the protoplast separated into two nearly equal halves, both of which contained chloroplasts, but only one of which contained a nucleus. The nucleated half of the cell senesced at the expected time, whereas senescence in the enucleated half was substantially retarded, as indicated by the fact that the chloroplasts in the enucleated half remained green and photosynthetic (65) (Fig. 3).



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Fig. 3. Senescence is under nuclear control. Leaf cells are placed in a hypertonic solution, which sometimes results in the protoplast separating into two halves. Both halves contain chloroplasts, but only one half contains the nucleus. The nucleated half undergoes senescence at the normal time (shown by the fact that the chloroplasts become yellow as a result of chlorophyll degradation), but the enucleated half displays delayed senescence (shown by the fact that the chloroplasts are green and photosynthetic) (65).

 
Mutants with altered leaf senescence phenotypes have been identified in various plant species. Leaf senescence can be delayed or accelerated by certain mutations. In Arabidopsis, three early onset of leaf death (old) mutants named old1 through old3 (66) and two hypersenescence (hys) mutants (67) with an early leaf senescence phenotype have been isolated. Characterization of the OLD genes at the molecular level has not yet been accomplished, whereas HYS1 has been shown to encode a protein with a nuclear localization signal at the N terminus and transmembrane domains at the C terminus (67). It has been hypothesized that a mutation in HYS1 might somehow render the mutant plant more sensitive to sugars or more efficient in sugar signaling, resulting in the early initiation of senescence. The Arabidopsis mutants Atapg7 (68) and Atapg9 (69), in which the process of autophagy is affected, also display premature leaf senescence. Autophagy is a process by which bulk cytoplasmic components and organelles are sequestered in specialized autophagic vesicles during starvation and senescence. The vesicles are subsequently delivered to vacuoles/lysosomes for degradation so that the nutrients can be recycled (see Cuervo Perspective). Precocious chlorophyll loss is observed in the loss-of-function mutants Atapy7 and Atapy9, supporting a role for autophagy in leaf senescence (68, 69).

Mutants with a delayed leaf senescence phenotype have been actively sought, and dozens of such mutants have been found, most of which display alterations in chloroplast breakdown or ethylene insensitivity (70). In Arabidopsis, leaf senescence in the mutants det2 (71), etr1 (36), ein2/ore3, ore1, ore4, ore9 (37), and dls1 (72) is delayed. As discussed above, the det2 mutant is deficient in BR biosynthesis, and the etr1 and ein2/ore3 mutants are insensitive to ethylene. The identity of the gene affected by the ore1 mutation is unknown. ORE4 is a plastidyl ribosomal small subunit; the ore4 mutation reduces chloroplast photosynthetic activity, resulting in less sugar production, which presumably limits the metabolic rate in leaf cells (23). Metabolic rate has been suggested to control longevity in animals (73), as discussed above.

Protein degradation potentially plays an important role in controlling life span in many organisms (74) (see Gray Review). The Arabidopsis ORE9 gene encodes an F-box protein with leucine-rich repeats (75). An F-box protein is a component of the ubiquitin E3 ligase/SCF complex, which ubiquitinates specific protein substrates and thereby targets them for proteolysis (76). It is hypothesized that the ORE9 protein promotes leaf senescence by targeting a senescence suppressor for degradation (75). The Arabidopsis DLS1 gene encodes an arginyl-tRNA:protein arginyltransferase (tRNA, transfer RNA). Yeast and mammalian homologs of this enzyme, which function in the N-end rule proteolytic pathway, transfer arginine to the N terminus of proteins with N-terminal glutamyl or aspartyl residues to promote their degradation. The DLS1 gene has been knocked out in Arabidopsis by transferred DNA (T-DNA) insertion--a method that uses the fact that a segment of plasmid DNA from the infectious bacterium Agrobacterium tumefaciens is transferred to the plant genome during infection, potentially disrupting a plant gene. In the dsl1 mutant, leaf senescence progresses more slowly than in the wild-type plant in both age-dependent and dark-induced senescence, suggesting that proteolysis by the N-end rule pathway has an important physiological function in the progress of leaf senescence in plants (72).

Gene expression is required for leaves to senesce. Leaf senescence is accompanied by changes in gene expression. Specifically, the vast majority of genes that are expressed in green nonsenescing leaves are down-regulated, whereas others (the SAGs) are up-regulated during leaf senescence. Gene inactivation per se is not sufficient for causing senescence; rather, gene expression within leaf cells is required for senescence to proceed. This idea is supported by numerous findings, documented in a large body of literature, that show that inhibitors of RNA and protein synthesis such as actinomycin D and cycloheximide, respectively, can block the senescence process in a variety of plant species.

Thousands of genes are expressed during leaf senescence. As discussed above, leaf senescence is most likely driven by new gene expression. Therefore, during the past decade, much effort in the leaf senescence field has been directed toward the identification of SAGs. By using various approaches, including differential display, differential cDNA library screening, polymerase chain reaction-based cDNA subtraction, and enhancer trapping (for a discussion of enhancer trapping, see the Tower Perspective), more than 100 SAGs have been isolated from a variety of plant species such as Arabidopsis, asparagus, barley, maize, and soybean (19, 77). Recently, use of the genomics approach has led to the identification of thousands of potential SAGs. Microarray analysis of Arabidopsis cDNAs resulted in the identification of more than 1400 genes that are differentially expressed before and during leaf senescence; some of the genes are up-regulated with the progression of leaf senescence (77). In senescing aspen leaves, more than 5000 expressed sequence tags (ESTs) that are up-regulated with the progression of leaf senescence have been identified and appear to belong to 380 gene families, although it is unknown how many genes these ESTs might represent (78). By large-scale single-pass sequencing of a senescent Arabidopsis leaf cDNA library, we have established a leaf senescence-specific EST database that represents approximately 2500 unique genes. These genes may constitute the entire transcriptome of leaf senescence in Arabidopsis (79). The Arabidopsis genome encodes 25,000 to 27,000 genes. Therefore, nearly 10% of the Arabidopsis genes are associated with leaf senescence, which is consistent with a previous estimation based on the fact that approximately 10% of the Arabidopsis enhancer trap lines display senescence-specific reporter expression (50). These results suggest that leaf senescence is a complex process.

The functions of only a few SAGs are known. On the basis of the functional annotation system, in which a gene is automatically assigned to a specific functional group after comparing its domain(s) against predefined sequence databases (80), the 2500 SAGs in Arabidopsis can be classified into the following functional groups: metabolism (14.4%); signal transduction (12.0%); transcription (8.4%); cell rescue, defense, death, and aging (7.7%); protein destination (6.5%); transport facilitation (5.2%); energy (4.0%); cellular organization (3.5%); protein synthesis (2.8%); cellular transport and mechanisms (2.7%); plant development (0.9%); and others (1.0%). The remaining 31% of the SAGs belong to the "unknown proteins" category (79). It should be noted that the classifications are based on annotations only. In fact, functions for the vast majority of SAGs have not been determined biochemically and/or genetically. Exceptions include a phospholipase D{alpha} (PLD{alpha}) from Arabidopsis, which has been shown to play a role in ABA- and ethylene-induced senescence in detached leaves in experiments using antisense technology. Suppression of PLD{alpha} expression leads to the retardation of senescence in detached leaves treated with ABA or ethylene, but the suppression has little effect on the progression of natural leaf senescence (81). In addition, the protein encoded by the SAG101 gene has recently been shown to possess lipolytic acyl hydrolase activity. Antisense suppression of the gene's expression causes a delayed leaf senescence phenotype, whereas inducible overexpression of this gene leads to precocious senescence (82). It has been postulated that the SAG101 protein serves to facilitate membrane breakdown in senescing leaf cells. Although many lipolytic enzymes are expressed in young leaves (and senescing leaves), these enzymes display only low activity toward intact phospholipids bilayers. Expressed at the onset of senescence, SAG101 attacks membrane phospholipids, and this initial attack and the accompanying release of free fatty acids perturbs the bilayer structure of the membrane; the perturbed membrane bilayers are better substrates for lipid-degradating enzymes than are unperturbed membranes (83). The disintegration of the membrane leads to cell death.

The WRKY6 gene from Arabidopsis is another example of a SAG for which functional information is available. This gene encodes a transcription factor (84) that has been shown to regulate a set of genes whose promoters contain W-box sequences, including a gene encoding a receptor-like protein kinase called SIRK; SIRK is strongly up-regulated during leaf senescence. The WRKY6 protein also negatively regulates expression from its own gene. Although WRKY6 clearly plays an important role in controlling gene expression during leaf senescence, for reasons that are not yet understood, a null mutation in this gene does not produce a significantly altered leaf senescence phenotype (85).

Regulation of SAG expression is complex. The complexity of gene regulation during leaf senescence comes from the fact that multifarious environmental cues and endogenous factors can induce leaf senescence. The large number of different types of genes that are associated with leaf senescence also suggests that the regulation of leaf senescence is an intricate process. For example, as discussed above, the genes specifically transcribed during leaf senescence in Arabidopsis include 134 genes that encode various transcription factors (84, 86) and 182 genes whose products are components of signal perception and transduction pathways, such as receptor-like kinases and kinases that act in mitogen-activated protein kinase cascades (79). Analyses of the expression of a limited number of SAGs during natural leaf senescence have revealed that different SAGs exhibit different temporal expression patterns and on that basis can be grouped into distinct classes (19, 87, 88). In addition, the patterns of SAG expression change in response to different conditions or treatments (89, 90). Bioinformatic analysis of promoter sequences of dozens of SAGs did not reveal conserved common cis-acting elements in their promoter regions, suggesting that the regulation of SAG expression is multifactorial. Furthermore, a 30-bp element in the promoter of SAG12 (25) and two cis elements in the promoter of OPR1 (a SAG regulated by JA) (91, 92) have been shown to be required for up-regulation of these genes during senescence, but do not share any sequence similarity with each other or with the W-box (TGACC/T) sequence bound by the transcription factor WRKY6 (85). Because there are so many leaf senescence-associated genes that encode transcription factors, and each transcription factor may bind to a unique cis element in the promoter of target genes, it is not surprising that no common cis element has been found. It is, however, expected that a subset of genes regulated by an identical transcription factor should share a conserved cis element(s), which may be revealed by extensive bioinformatics analysis of promoter sequences of the many SAGs in Arabidopsis.

It is now generally accepted that there may be multiple postmitotic senescence-associated regulatory pathways that activate distinct sets of genes, and that certain genes may be shared by two, three, or more pathways, in such a way that they are interconnected to each other to form a convoluted regulatory network (Fig. 4). He et al. systematically analyzed the regulation of the leaf senescence-specific expression of a reporter construct in 125 Arabidopsis enhancer trap lines by six senescence-promoting factors, including ABA, ethylene, JA, BR, darkness, and dehydration (50). These researchers found that the expression of the individual SAGs, as represented by expression of the reporter gene of the enhancer trap cassette, is distinctly regulated by one, two, or more of these factors. Because a gene regulated by one factor is likely to be in the upstream portion of the proposed regulatory network, whereas a gene regulated by multiple stimuli may function in the downstream portion of the network, the authors were able to place individual genes and enhancer trap lines in the proposed network (50).



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Fig. 4. Conceptual model of a regulatory network that controls leaf senescence. Multiple pathways that respond to various environmental cues and endogenous factors, including age and reproductive growth (RG), are possibly interconnected to form a regulatory network. ("Sink" refers to actively growing tissues such as developing fruits and seeds that drain nutrients from the leaf and other tissues.) The factors and signals are likely perceived and transmitted by different signal transduction pathways, which in turn activate various subsets of SAGs via leaf senescence-associated transcription factors. Cross-talk might occur among signaling pathways. The expression of many SAGs is believed to lead to the execution of senescence. The leaf senescence antagonists (the cytokinins and the polyamines) are likely to suppress the expression of SAGs. Recent studies in Arabidopsis suggest that this network may involve approximately 2500 genes (see text for details) (79).

 

Closing Remarks Back to Top

As do animal cells, plants exhibit both mitotic and postmitotic senescence. Although mitotic (replicative or proliferative) senescence in plants has been much less studied than the comparable processes in yeasts and animals, substantial progress has been made toward understanding the underlying molecular mechanisms. It is known that, unlike in animals, telomere length and telomerase do not play a role in modulating plant mitotic senescence, as revealed by analyzing telomerase knockout mutants in Arabidopsis.

In contrast to mitotic senescence, much progress has been made toward the understanding of postmitotic senescence in plants at the molecular level, particularly of leaf senescence. Many factors are known to regulate this genetically controlled process. Dozens of leaf senescence mutants have been isolated and characterized, and some of the relevant genes have been cloned. Approximately 2500 genes that are expressed in senescing leaves in Arabidopsis have been identified, and a few of the genes have been functionally characterized. Current studies have revealed that the regulation of leaf senescence is complex and likely involves a complicated network. These studies have laid a solid foundation for unraveling the molecular regulatory mechanisms underlying leaf senescence. In order to fully understand leaf senescence, it is necessary to continue characterizing the many SAGs, especially those encoding transcription factors and those encoding components of signal transduction pathways, by using various functional genomics approaches. Although approaches that allow the analysis of the loss of function of a given gene (such as T-DNA knockout and antisense/RNA interference knockdown techniques) have been useful in deciphering gene function, analysis of gain-of-function mutations is also important for assigning functions to genes. This is especially true when or if the loss-of-function analysis does not reveal any phenotypic, physiological, biochemical, and/or molecular changes, as a result of genetic redundancy, for example. In addition to understanding gene function, it is also necessary to investigate how these genes are coordinately expressed during senescence. Perhaps the first task in this regard is to unravel the leaf senescence-specific transcription factor network by using DNA microchip and chromatin immunoprecipitation approaches (see Vaquero Review). Once the regulatory mechanisms of leaf senescence are understood, it will be possible to devise ways to delay leaf senescence for increased CO2 fixation (and thus increased crop yield). A better understanding of how to delay senescence might also allow us to store fresh vegetables longer. Understanding the regulatory mechanisms of leaf senescence might also shed light on the molecular mechanisms of aging in general, because one of the important factors controlling leaf senescence in Arabidopsis is age.


September 24, 2003
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  93. I thank past and current members of the Gan Laboratory for stimulating discussions. Our research on plant senescence has been supported by grants from the U.S. Department of Energy Bioenergy Sciences, U.S. Department of Agriculture National Research Initiative, Cornell Genomics Initiative, and Kentucky Tobacco Research and Development Center at the University of Kentucky.
Citation: S. Gan, Mitotic and Postmitotic Senescence in Plants. Sci. SAGE KE 2003 (38), re7 (2003).








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