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American Society of Plant Biologists
"Cross-Talk" between Cell Division Cycle and Development in Plants
a Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid Cantoblanco, E-28049 Madrid, Spain bboniotti{at}cbm.uam.es The elaboration of plant form and function depends on the ability of a plant cell to divide and differentiate. The decisions of individual cells to enter the cell cycle, maintain proliferation competence, become quiescent, expand, differentiate, or die depend on the perception of various signals. These signals can include hormones, nutrients, light, temperature, and internal positional and developmental cues. The title "Cross-Talk between Cell Division Cycle and Development in Plants" was chosen for a workshop hosted by the Instituto Juan March de Estudios e Investigaciones in Madrid (Spain) from November 12 to 14, 2001, and cosponsored by the Institute of Molecular Agrobiology, Singapore, to address the age-old question of whether cells make plants or plants make cells. The mainstream ideas that emerged indicated that the activity of key cell cycle regulators (controlling cell cycle transitions) also can have profound effects on development. Here, we highlight a number of new discoveries reinforcing this idea. The widely conserved cyclin-dependent kinases (CDKs) and their cyclin (Cyc) partners are the driving forces of cell cycle progression, regulating the G1/S- and G2/M-phase transitions as well as progression through and exit from the cell cycle (Figure 1) . It is accepted that in plants, CDK/cyc complexes phosphorylate the retinoblastoma-related protein (RBR), causing the activation of a set of genes that are regulated by the E2F/DP transcription factor and are necessary for S-phase entry and DNA replication. Later in G2, the activity of other CDK/cyc complexes induce entry into mitosis. During M-phase, the degradation of the mitotic cyclins and the deactivation of the kinase complexes permit exit from mitosis. CDK activity is controlled strictly and temporally by factors such as CDK inhibitors and cdc2-activating kinases. Almost all of these regulatory proteins have been identified in different plant species.
The plant CycD gene family (consisting of CycD1 to CycD4) seems to have a special function in communicating external signals to the cells. In Arabidopsis, CycD2 and CycD4 respond to sugar availability, whereas CycD3 responds to cytokinins and brassinosteroids. The idea that CycD3 is an important regulator of leaf development in both Arabidopsis and snapdragon (Antirrhinum) emerged on the basis of work presented by Jim Murray (Institute of Biotechnology, Cambridge, UK) and John Doonan (John Innes Centre, Norwich, UK), respectively. Overexpression of Arabidopsis CycD3-1 affects leaf development, leading to curled leaves with an increased number of smaller cells and partial loss of cellu-lar organization (Meijer and Murray, 2001  ). Doonan showed that snapdragon CycD3a, but not CycD3b or CycB2, is upregulated specifically in the first formed leaves of the phantastica (phan) mutant. This also corresponds to an increase in leaf cell number compared with that of wild type. Even so, overexpressing CyCD3a under the 35S promoter of Cauliflower mosaic virus in Arabidopsis did not phenocopy the Arabidopsis mutant ortholog of phan, asymmetric leaves1, suggesting that altered CycD3a activity might not be the sole contributor to the phan mutant phenotype. This is not altogether surprising, because PHAN probably is high within the regulatory hierarchy that controls leaf growth and development.
Andrew Fleming (Institute of Plant Sciences, Zürich, Switzerland) investigated the effects of transiently increasing cell proliferation during leaf morphogenesis in tobacco. The technique involved microapplication of an inducer to briefly overexpress the fission yeast gene Cdc25 or a plant CycA (either of which is expected to accelerate the entry of cells into mitosis by activating CDKs). When induced solely on the margins of tobacco leaf primordia, there was an initial localized increase in cell division, but the division pattern did not conform to that of the wild type. In contrast to the lines constitutively overexpressing CycD3, the phenotype of the mature leaves showed a deple-tion of lamina outgrowth: the blades consisted of fewer but larger cells (Wyrzykowska et al., 2002
Deregulated expression of downstream targets of CDK/cyc activity also has effects at both the organ and cellular levels. Dirk Inzé (Flanders Inter-university for Biotechnology, Ghent, Belgium) reported that transgenic plants co-overexpressing members of the E2F and DP family of transcription factors show a leaf phenotype that is similar to, but more severe than, that of the CycD3-overexpressing lines. In contrast, leaves overexpressing the Arabidopsis CDK inhibitors KRP1 and KRP2 (Kip-related proteins), the negative regulators of CDK/cyc complexes, produce 10-fold fewer leaf cells (De Veylder et al., 2001
During G2-phase, B-type cyclins are required to activate the CDK activity that triggers the entry into mitosis. Their expression is determined by an M-specific activator (MSA) sequence present in the CycB promoters. John Doonan and Masaki Ito (University of Tokyo, Tokyo, Japan) reported the isolation of three different Myb-like transcription factors (NtMybA1, NtMybA2, and NtMybB) that recognize MSA sequences in tobacco (Ito et al., 2001 ). Although NtMybB is expressed constitutively during the cell cycle, NtMybA is coexpressed with CycB in G2/M-phase. They also reported that in tobacco protoplasts, NtMybA1 and NtMybA2 activated the MSA-containing promoters, whereas NtMybB repressed them. Doonan and Ito concluded that temporally controlled plant B-type cyclin expression can be a balance between constitutively NtMybB repression and temporally controlled NtMybA1 activation. Many, but not all, G2/M-expressed genes contain MSA elements, so this finding could provide a mechanism to coordinate the temporal expression of a cohort of such genes. The Destruction (D)-box proteolytic pathway is believed to be required for the exit from mitosis. The components of this pathway are the ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2), and the ubiquitin protein ligase (E3), which in the case of mitotic cyclin is thought to be the anaphase-promoting complex (APC). Pascal Genschik (Institut de Biologie Moléculaire des Plantes du Centre National de la Recherche Scientifique, Cédex, France) reported that in tobacco, both NtCycA3-1 and NtCycB1-1 proteins contain a D-box important for their phase-specific proteolysis. He also described the isolation of two different D-box–specific ubiquitin-conjugating enzymes in Arabidopsis, E2C1 and E2C2. They present different expression profiles, and considering the fact that E2C2 is expressed also in differentiated cells, this suggests that D-box–like activity is not restricted only to proliferating cells but is maintained in differentiated tissues, as occurs in human postmitotic neurons.
The occurrence of repeated rounds of DNA replication in the absence of mitosis is a process commonly associated with cell differentiation in plants. One way to induce endoreduplication is to inhibit the mitotic CDK/cyclin complexes before the M-phase transition point. This can be achieved by early activation of the APC proteolytic pathway, an activity usually restricted to late metaphase. Eva Kondorosi (Institut des Sciences du Végétales, Gif-sur-Yvette, France) described the isolation of two different APC activators, ccs52A and ccs52B, from Medicago truncatula and Arabidopsis. Although MtCcs52A clearly is involved in endoreduplication and symbiotic cell differentiation during nodule development, the function of MtCcs52B remains unknown. The different expression profiles in alfalfa (M. sativa) synchronized cells, shown by promoter–
Trichomes provide a good developmental model with which to study the regulation of endoreduplication. Arp Schnittger (Max-Planck-Institut für Züch-tungsforschung, Köln, Germany) showed that during early trichome development, when endoreduplication commences, expression of the mitotic cyclins CycB1-1 and CycB1-2 is no longer detectable. Furthermore, he showed that by expressing CycB1-2 ectopically, trichomes could induce mitotic cycling, generating two- or three-celled trichomes. Despite this finding, the DNA content overall was not grossly different from the 32C usually found in mature trichomes. The Arabidopsis siamese (SIM) mutant has a similar, but more severe, trichome phenotype (Walker et al., 2000
The activation of DNA replication in S-phase depends on the activity of prereplicative complexes. The coordinated function of their components (CDC6 and ORC among others) is important for the once-per-cell-cycle DNA replication control. Crisanto Gutierrez (Centro de Biología Molecular, Madrid, Spain) showed that Arabidopsis CDC6 seems to be an E2F/DP target and is expressed in both proliferating and endoreplicating cells (e.g., trichomes). Fur-thermore, its overexpression induces extra rounds of endoreduplication in leaf cells (Castellano et al., 2001
Hormones play vital roles in different aspects of plant growth from cell division to development. In Arabidopsis, a collection of auxin response mutants was isolated by Mark Estelle (University of Texas, Austin). Among them, the tir1 (for auxin transport inhibitor resistant) mutant is deficient in a variety of auxin-regulated growth processes, such as lateral root formation. The TIR1 gene encodes an F-box protein, one of the four subunits of the ubiquitin protein ligase (SCF complex) that confers target specificity. The other subunits are the scaffold components Skp-like proteins (ASK), Cullin (CUL), and the RBX protein.
Several presentations highlighted the role of ubiquitin-mediated proteolysis as a common pathway in plant hormone signaling. Estelle reported that some of the targets of SCFTIR1-dependent degradation are the auxin/indoleacetic acid (Aux/IAA) transcription factors, whose turnover (as shown for AXR2 and AXR3) is induced by auxin. The model proposed suggests that heterodimers of Aux/IAA and auxin response factors normally block the transcription of target genes. Only when the Aux/IAA factor is degraded does the auxin response factor acti-vate transcription (Gray et al., 2001
Another example was presented by Nam-Hai Chua (Rockefeller University, New York, and Institute of Molecular Agrobiology, Singapore). NAC1 is a transcription factor that is induced by auxin and that activates genes required for lateral root development. Genetic analysis places NAC1 downstream of TIR1 in transmitting the auxin signal (Xie et al., 2000 Ben Scheres (Utrecht University, The Netherlands) talked about the HOBBIT (HBT) gene in relation to auxin response in Arabidopsis roots. The HBT protein is required to generate the founder cell of the root meristem, and it is likely to be a component of the APC. Consistent with this function, CycB2 and HBT expression colocalize in individual embryo cells. Interestingly, hbt mutants show an altered expression pattern of auxin reporter genes, suggesting that APC-mediated proteolysis also is involved in auxin response. Moreover, four new genes that control the development of the columella and lateral root cap were identified, and initial studies suggest that they act downstream of auxin-mediated patterning mechanisms in Arabidopsis root meristems.
Two main issues arise when using a classic genetics approach to study cell cycle genes in plants. First, multiple copies of genes may mask a mutant phenotype; for example, CycD3 knockouts in Arabidopsis show no phenotypic abnormalities (V. Sundaresan and H.S. Kwee, personal communication). Second, essential genes may not be recovered because gametes carrying such mutant alleles could be inviable or die (which possibly explains why no RBR mutant has been recovered in plants). Some essential cell cycle genes, however, have been identified in mutant screens and have been found to play vital roles during gametogenesis or embryogenesis. In the majority of angiosperms, during the development of the female gametophyte only one product of meiosis survives, whereas the other three undergo programmed cell death. The remaining haploid cell then proceeds through three rounds of mitosis without cytokinesis (generating eight nuclei) before maturing as a cellularized embryo sac. Wei-Cai Yang (Institute of Molecular Agrobiology) described an Arabidopsis mutant in which more than one of the meiotic products appears to survive, resulting in an ovule with multiple embryo sacs. The protein affected is essential for cell cycle progression in yeast. However, in this case, it is unclear whether the failure to always induce cell death in the other three meiotic products is caused by the overexpression of, or a reduction in, gene activity. Venkatesan Sundaresan (University of California, Davis, and Institute of Molecular Agrobiology) described an Arabidopsis mutant of cdc16, which encodes a protein that forms part of the APC complex required for mitotic progression. The mutant undergoes meiosis, but results in arrest of the female gametophyte after the first mitotic division. Sundaresan also described a novel embryo lethal mutant, tormoz. These embryos often fail to undergo longitudinal divisions during early development; instead, the division planes are transverse or oblique, leading to abnormal embryos. The disrupted gene codes for a unique WD-40 repeat protein that localizes to the nucleus but has no putative function. Ueli Grossniklaus (Institute of Plant Biology, Zürich, Switzerland) described two gametophytic mutants, hadad (hdd) and haumea (hma), that affect cell division in the embryo sac. The mutants usually do not complete the series of mitotic divisions, but cellularization of the embryo sac still occurs occasionally. Rarely, excessive postmeiotic cell divisions occur in both mutants (producing as many as 32 nuclei), suggesting that they are defective in the regulation of cell division rather than in a basic cellular function. In hma, enlarged nuclei are common, suggesting the occurrence of endoreduplication cycles. The hma phenotype cosegregates with a Ds insertion in a gene encoding a large predicted transmembrane protein containing leucine-rich repeats, suggesting a role in cell signaling.
Gerd Jürgens (Universität Tübingen, Germany) described a series of Arabidopsis embryo mutants that contain multinucleate cells that are unable to complete cytokinesis. This wine-winning presentation showed the involvement of a cytokinesis-specific SNARE complex required for vesicle fusion at the plane of cell division. It is a trimeric complex consisting of a syntaxin (KNOLLE), a SNAP25 homolog (AtSNP33), and a synaptobrevin (as yet unidentified), which enables lateral expansion of the cell plate (Heese et al., 2001
David Meinke (Oklahoma State University, Stillwater) reported the cloning of several TITAN (TTN) genes in collaboration with Syngenta (Research Triangle Park, NC) (McElver et al., 2001
Plant cell patterning and cell fate determination seem to be controlled by positional signals during the early stages of embryogenesis. Such signals are important for dictating the expression of specific transcription factors, but their stable transcription is ensured later by cell-autonomous mechanisms. The data we report here suggest the importance of chromatin remodeling and chromatin assembly in the control of plant development through the maintenance of epigenetic gene expression states. Several Arabidopsis mutants with defects in chromatin remodeling factors have been identified. Recently, Kaya et al. (2001) reported the cloning of two genes, called FAS1 and FAS2, encoding the two largest subunits of chromatin assembly factor-1 (CAF-1). fas1 and fas2 mutants exhibit a similar altered organization of the shoot and root apical meristems. FAS1 and FAS2 proteins interact with AtMSI1, a WD-40 repeat protein, and together they show replication-dependent nucleosome assembly activity, suggesting that FAS1, FAS2, and AtMSI1 are the functional counterparts of the p150, p60, and p48 subunits of human CAF1, respectively. MSI1 proteins seem to play a crucial role in the formation of different multiprotein complexes. Wilhelm Gruissem (Institute of Plant Sciences) reported that plants underexpressing AtMSI1 show alterations in growth patterns and growth rates from the early stages of development. Interestingly, the phenotype becomes more severe as the plants age, suggesting a role for MSI1 in maintaining proper developmental states through successive rounds of cell division. MSI1 in the CAF1 complex may contribute to establishing and maintaining the state of gene expression and/or repression in the apical meristems. CAF possibly ensures the inheritance/propagation of epigenetic chromosomal states by facilitating chromatin assembly during DNA replication.
Ueli Grossniklaus showed that the MEDEA (MEA) and FERTILIZATION-INDEPENDENT ENDOSPERM (FIE) genes are coexpressed during seed development and that the proteins interact in yeast and in vitro (Spillane et al., 2000 José Martínez-Zapater (Centro Nacional de Biotecnología, Madrid, Spain) described the positional cloning of FVE, a locus in the autonomous flowering promotion pathway of Arabidopsis. Mu-tations at the FVE locus cause a delay in flowering time correlated with the upregulation of FLOWERING LOCUS C (FLC), a putative floral repressor. FVE encodes a different member of MSI family, AtMSI4, and could be involved in the negative regulation of FLC via histone modification.
The role of cell wall expansion in the induction of the cell cycle was investigated by Andrew Fleming (see above). When expression of a plant expansin was induced on the flank of a shoot apical meristem in tobacco, it was sufficient to stimulate de novo development of a morphologically normal leaf primordium. The only detectable effect on the meristem was to alter the shoot developmental program by reversing the phyllotaxy (Pien et al., 2001 ). When expansin production was stimulated transiently on the side of an emerging leaf primordium (P2/P3 stage), it resulted in significant expansion of the lamina in mature leaves. Interestingly, the larger leaf blade contained more cells having normal morphology rather than cells that had expanded in size. These results imply that there is feedback regarding cell size to the cell cycle such that expanded cells may promote the entry into mitosis and newly formed cells then are incorporated into the usual differentiation program. Therefore, because the rate of cell expansion can influence cellular proliferation rates, it also becomes a potential indirect regulator of organ size (Mizukami, 2001). One technique that has great potential to enhance our understanding of the relationships between cell identity, cell division, and pattern formation was presented by Jan Traas (Institut National de la Recherche Agronomique, Versailles, France). He and his colleagues have devised a system to visualize growth patterns in living Arabidopsis meristems. The example presented showed the induction of a green fluorescent protein reporter gene driven by promoters of genes that identify floral meristems at inception, such as AINTEGUMENTA and LEAFY. After following the pattern of the incipient flower primordia for several days, they showed that cells are initially recruited asynchronously. This occurs very rapidly, without any visible changes in the pattern of cell division. When a threshold number of cells have adopted the same identity, a change in cell expansion and cell division results in the emergence of a primordium. It will be of interest to combine this system with different mutants or in backgrounds in which other gene-specific promoters drive a different reporter gene. It also will be of particular interest to study mutants defective in organ development. One such mutant, strubbelig (presented by Kay Schneitz, Institute of Plant Biology) unpredictably shows either an expanded or depleted inflorescence meristem and produces flowers without the full complement of organs. It is now possible to ask whether the reduction in organ size or missing organs is caused by the failure to reach the threshold number of cells or whether the cells fail to initiate an organ identity program.
Castellano, M.M., del Pozo, J.C., Ramirez-Parra, E., Brown, S., and Gutierrez, C. (2001). Expression and stability of Arabidopsis CDC6 is associated with endoreplication. Plant Cell 13, 2671–2686.
De Veylder, L., Beeckman, T., Beemster, G.T., Krols, L., Terras, F., Landrieu, I., van der Schueren, E., Maes, S., Naudts, M., and Inze, D. (2001). Functional analysis of cyclin-dependent kinase inhibitors of Arabidopsis. Plant Cell 13, 1653–1668. Gray, W.M., Kepinski, S., Rouse, D., Leyser, O., and Estelle, M. (2001). Auxin regulates SCFTIR1-dependent degradation of AUX/IAA proteins. Nature 414, 271–276.[CrossRef][Medline]
Heese, M., Gansel, X., Sticher, L., Wick, P., Grebe, M., Granier, F., and Jürgens, G. (2001). Functional characterization of the KNOLLE-interacting t-SNARE AtSNAP33 and its role in plant cytokinesis. J. Cell Biol. 155, 239–250.
Ito, M., Araki, S., Matsunaga, S., Itoh, T., Nishihama, R., Machida, Y., Doonan, J.H., and Watanabe, A. (2001). G2/M-phase–specific transcription during the plant cell cycle is mediated by c-Myb–like transcription factors. Plant Cell 13, 1891–1905. Kaya, H., Shibahara, K., Taoka, K., Iwabuchi, M., Stillman, B., and Araki, T. (2001). FASCIATA genes for chromatin assembly factor-1 in Arabidopsis maintain the cellular organization of apical meristems. Cell 104, 131–142.[CrossRef][ISI][Medline] Liu, C.M., McElver, J., Tzafrir, I., Joosen, R., Wittich, P., Patton, D., Van Lammeren, A.A.M., and Meinke, D.W. (2002). Condensin and cohesin knockouts in Arabidopsis exhibit a titan seed phenotype. Plant J., in press.
McElver, J., et al. (2001). Insertional mutagenesis of genes required for seed development in Arabidopsis thaliana. Genetics 159, 1751–1763. Meijer, M., and Murray, J.A.H. (2001). Cell cycle controls and the development of plant form. Curr. Opin. Plant Biol. 4, 44–49.[CrossRef][ISI][Medline] Mizukami, Y. (2001). A matter of size: Developmental control of organ size in plants. Curr. Opin. Plant Biol. 4, 533–539.[CrossRef][ISI][Medline]
Pien, S., Wyrzykowska, J., McQueen-Mason, S., Smart, C., and Fleming, A. (2001). Local expression of expansin induces the entire process of leaf development and modifies leaf shape. Proc. Natl. Acad. Sci. USA 98, 11812–11817. Spillane, C., MacDougall, C., Stock, C., Kohler, C., Vielle-Calzada, J.P., Nunes, S.M., Grossniklaus, U., and Goodrich, J. (2000). Interaction of the Arabidopsis polycomb group proteins FIE and MEA mediates their common phenotypes. Curr. Biol. 10, 1535–1538.[CrossRef][ISI][Medline] Strompen, G., El Kasmi, F., Richter, S., Lukowitz, W., Assaad, F.F., Jürgens, G., and Mayer, U. (2001). The Arabidopsis HINKEL gene encodes a kinesin-related protein involved in cytokinesis and is expressed in a cell cycle–dependent manner. Curr. Biol., in press. Tzafrir, I., McElver, J., Liu, C.M., Yang, L.J., Wu, J.Q., Martinez, A., Patton, D., and Meinke, D. (2002). Diversity of TITAN functions in Arabidopsis seed development. Plant Physiol. 128, in press. Walker, J.D., Oppenheimer, D.G., Concienne, J., and Larkin, J.C. (2000). SIAMESE, a gene controlling the endoreduplication cell cycle in Arabidopsis thaliana trichomes. Development 127, 3931–3940.[Abstract] Wyrzykowska, J., Pien, S., Shen, W.H., and Fleming, A.J. (2002). Manipulation of leaf shape by modulation of cell division. Development, in press.
Xie, Q., Frugis, G., Colgan, D., and Chua, N.H. (2000). Arabidopsis NAC1 transduces auxin signal downstream of TIR1 to promote lateral root development. Genes Dev. 14, 3024–3036. This article has been cited by other articles:
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G1/S REGULATORS
G2/M TRANSITION,...
-glucuronidase activity, in-dicate that the different CCS52 members are linked to distinct developmental processes and/or to differentiation of specific cell types. 
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