Geminin Coordinates Cell Cycle and Developmental Control

Growth and differentiation are two major themes in embryonic development. Numerous cell divisions have to be regulated on the path from a unicellular embryo, the zygote, to the multicellular structures of a mature being. Numerous functions, specializations and cellular identities have to be generated, in order to form a complex and mature animal. Numerous mechanisms have to control the correct assignment and acquisition of cellular fates, as well as the right timing and allocation of cells. Therefore, a strict coordination has to occur between embryonic patterning and the cell cycle. From this point of view, dual roles or mutual interactions of typical proliferation and developmental control genes are likely. Recently, new light was shed on these issues by identifying the nuclear protein Geminin as a molecular coordinator between the cell cycle and axial patterning. We summarize the role of Geminin in cell cycle, in the embryonic patterning controlled by Hox genes, providing insights into cell cycle regulators in embryonic development, and, conversely, typical developmental control genes in cell cycle regulation.     

Cell cycle regulation in higher plants

The isolation of plant genes homologous to cdk and cyclin components from yeast and animals proves the existence of a basic cell cycle machinery in all eukaryotes. cdk and cyclin expression has been shown to be involved in the spatial and temporal control of cell division in a variety of developmental processes. In plants, cell division and development are closely interlinked processes that are regulated by phytohormones. cdks and cyclins were found to be under control of phytohormones underscoring their integral role in mediating different developmental pathways. Furthermore, studies on cdk and cyclin expression not only correlate with actual cell cycle activity but also with cell division competence providing a working model to understand regeneration capacity at the molecular level.     

Emerging roles of RETINOBLASTOMA-RELATED proteins in evolution and plant development

RETINOBLASTOMA-RELATED (RBR) proteins are plant homologs of the human tumor suppressor pRB. Similar to their animal counterparts they have roles in cell cycle regulation and differentiation. We discuss recent findings of the evolution of RBR functions ranging from a molecular ruler and metabolic integrator in algae to a coordinator of differentiation in gametophytes. Genetic analysis and manipulation of protein levels during gametophytic and post-embryonic plant development are now providing new insights into the function of RBR in stem cell maintenance, cell specification and differentiation. We briefly explain interactions of RBR with chromatin-modifying complexes that appear to be a central underlying molecular mechanism during developmental transitions.     

Getting in the Loop: Regulation of Development in Caulobacter crescentus

Summary: Caulobacter crescentus is an aquatic Gram-negative alphaproteobacterium that undergoes multiple changes in cell shape, organelle production, subcellular distribution of proteins, and intracellular signaling throughout its life cycle. Over 40 years of research has been dedicated to this organism and its developmental life cycles. Here we review a portion of many developmental processes, with particular emphasis on how multiple processes are integrated and coordinated both spatially and temporally. While much has been discovered about Caulobacter crescentus development, areas of potential future research are also highlighted.     

lin-35/Rb and ubc-18, an E2 ubiquitin-conjugating enzyme,function redundantly to control pharyngeal morphogenesis in C. elegans

The retinoblastoma gene product has been implicated in the regulation of multiple cellular and developmental processes, including a well-defined role in the control of cell cycle progression. The Caenorhabditis elegans retinoblastoma protein homolog, LIN-35, is also a key regulator of cell cycle entry and, as shown by studies of synthetic multivulval genes, plays an important role in the determination of vulval cell fates. We demonstrate an additional and unexpected function for lin-35 in organ morphogenesis. Using a genetic approach to isolate lin-35 synthetic-lethal mutations, we have identified redundant roles for lin-35 and ubc-18, a gene that encodes an E2 ubiquitin-conjugating enzyme closely related to human UBCH7. lin-35 and ubc-18 cooperate to control one or more steps during pharyngeal morphogenesis. Based on genetic and phenotypic analyses, this role for lin-35 in pharyngeal morphogenesis appears to be distinct from its cell cycle-related functions. lin-35 and ubc-18 may act in concert to regulate the levels of one or more critical targets during C. elegans development.     

Interactions between the developmental program and cell cycle regulation of Aspergillus nidulans

Aspergillus nidulans is a multicellular fungus being used to study developmental regulation and cell cycle regulation. Genetic and molecular mechanisms underlying both processes have been characterized. Two types of observations suggest that there is significant interaction between cell cycle and developmental regulatory mechanisms. First, A. nidulans development involves the formation of specialized cell types that contain different, but specific, numbers of nuclei that are differentially regulated for cell cycle progression. Second, mutations directly affecting nuclear division can have major affects on cell differentiation during development. In this essay we describe these interactions and point out potential mechanisms for the cross talk between morphogenesis and the cell cycle that are tractable for future experimental investigation.     

Cell cycle timing and developmental checkpoints in Caulobacter crescentus

Development in Caulobacter reflects a level of complexity once thought only to exist in eukaryotic cells. The cell cycle and development are not isolated from each other, but are interdependent processes. Checkpoints are in place to ensure that both cell cycle and developmental processes are completed accurately before the next stage is initiated. The timing of these processes is regulated by signal transduction networks that integrate signals from DNA replication, cell division and development. These signal transduction networks achieve precise timing of the cell cycle and development by regulating temporal gene expression, and protein activity by dynamic spatial localization within the cell and timed proteolysis.     

Small organelle,big responsibility: the role of centrosomes in development and disease

The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.     

Developmental analysis of maize endosperm proteome suggests a pivotal role for pyruvate orthophosphate dikinase

Although the morphological steps of maize (Zea mays) endosperm development are well described, very little is known concerning the coordinated accumulation of the numerous proteins involved. Here, we present a proteomic study of maize endosperm development. The accumulation pattern of 409 proteins at seven developmental stages was examined. Hierarchical clustering analysis allowed four main developmental profiles to be recognized. Comprehensive investigation of the functions associated with clusters resulted in a consistent picture of the developmental coordination of cellular processes. Early stages, devoted to cellularization, cell division, and cell wall deposition, corresponded to maximal expression of actin, tubulins, and cell organization proteins, of respiration metabolism (glycolysis and tricarboxylic acid cycle), and of protection against reactive oxygen species. An important protein turnover, which is likely associated with the switch from growth and differentiation to storage, was also suggested from the high amount of proteases. A relative increase of abundance of the glycolytic enzymes compared to tricarboxylic acid enzymes is consistent with the recent demonstration of anoxic conditions during starch accumulation in the endosperm. The specific late-stage accumulation of the pyruvate orthophosphate dikinase may suggest a critical role of this enzyme in the starch-protein balance through inorganic pyrophosphate-dependent restriction of ADP-glucose synthesis in addition to its usually reported influence on the alanine-aromatic amino acid synthesis balance.     

Maintenance of imaginal disc plasticity and regenerative potential in Drosophila by p53

Following irradiation (IR), the DNA damage response (DDR) activates p53, which triggers death of cells in which repair cannot be completed. Lost tissue is then replaced and re-patterned through regeneration. We have examined the role of p53 in co-regulation of the DDR and tissue regeneration following IR damage in Drosophila. We find that after IR, p53 is required for imaginal disc cells to repair DNA, and in its absence the damage marker, γ-H2AX is persistently expressed. p53 is also required for the compensatory proliferation and re-patterning of the damaged discs, and our results indicate that cell death is not required to trigger these processes. We identify an IR-induced delay in developmental patterning in wing discs that accompanies an animal-wide delay of the juvenile-adult transition, and demonstrate that both of these delays require p53. In p53 mutants, the lack of developmental delays and of damage resolution leads to anueploidy and tissue defects, and ultimately to morphological abnormalities and adult inviability. We propose that p53 maintains plasticity of imaginal discs by co-regulating the maintenance of genome integrity and disc regeneration, and coordinating these processes with the physiology of the animal. These findings place p53 in a role as master coordinator of DNA and tissue repair following IR.     

The cell cycle gene MoCDC15 regulates hyphal growth, asexual development and plant infection in the rice blast pathogen Magnaporthe oryzae

Rice blast, caused by the pathogen Magnaporthe oryzae, is a serious hindrance to rice production and has emerged as an important model for the characterization of molecular mechanisms relevant to pathogenic development in plants. Similar to other pathogenic fungi, conidiation plays a central role in initiation of M.oryzae infection and spread over a large area. However, relatively little is known regarding the molecular mechanisms that underlie conidiation in M. oryzae. To better characterize these mechanisms, we identified a conidiation-defective mutant, ATMT0225B6 (MoCDC15(T-DNA)), in which a T-DNA insertion disrupted a gene that encodes a homolog of fission yeast cdc15, and generated a second strain containing a disruption in the same allele (ΔMoCDC15(T-DNA)). The cdc15 gene has been shown to act as a coordinator of the cell cycle in yeast. Functional analysis of the MoCDC15(T-DNA) and ΔMoCDC15(T-DNA) mutants revealed that MoCDC15 is required for conidiation, preinfection development and pathogenicity in M. oryzae. Conidia from these mutants were viable, but failed to adhere to hydrophobic surface, a crucial step required for subsequent pathogenic development. All phenotypic defects observed in mutants were rescued in a strain complemented with wild type MoCDC15. Together, these data indicate that MoCDC15 functions as a coordinator of several biological processes important for pathogenic development in M. oryzae.     

Cell cycle controls and the development of plant form

The relationship between cell division and plant form has long been a battleground for the debate between those proclaiming and disclaiming an important role for cell division in morphogenetic and developmental processes. Recent evidence suggests that cell division and morphogenesis are intimately interconnected, and whereas overall architecture is determined by patterning genes, the elaboration and execution of developmental programmes require proper control of the cell-division cycle.     

Kinesin-7 CENP-E regulates cell division,gastrulation and organogenesis in development

Kinesin-7 CENP-E motor protein is essential for chromosome alignment and kinetochore-microtubule attachment in cell division. Human CENP-E has recently identified to be linked with the microcephalic primordial dwarfism syndromes associated with a smaller head, brain malformations and a prominent nose. However, the roles of CENP-E in embryonic development remain largely unknown. In this study, we find that zebrafish CENP-E inhibition results in defects in early zygote cleavage, including asymmetric cell division, cell cycle arrest and the developmental abnormalities. We also demonstrate that CENP-E ablation in cultured cells leads to chromosome misalignment, spindle abnormalities and interruptions of the cell cycle. These observations suggest that CENP-E plays a key role in early cell division and cell cycle progression. Furthermore, we also find that CENP-E inhibition results in the defects in the epiboly, the developmental arrest, the smaller head and the abnormal embryo during zebrafish embryogenesis. Our data demonstrate new functions of CENP-E in development and provide insights into its essential roles in organogenesis.     

Phytochrome coordinates Arabidopsis shoot and root development

The phytochrome family of photoreceptors are potent regulators of plant development, affecting a broad range of responses throughout the plant life cycle, including hypocotyl elongation, leaf expansion and apical dominance. The plant hormone auxin has previously been linked to these phytochrome-mediated responses; however, these studies have not identified the molecular mechanisms that underpin such extensive phytochrome and auxin cross-talk. In this paper, we show that phytochrome regulates the emergence of lateral roots, at least partly by manipulating auxin distribution within the seedling. Thus, shoot-localized phytochrome is able to act over long distances, through manipulation of auxin, to regulate root development. This work reveals an important role for phytochrome as a coordinator of shoot and root development, and provides insights into how phytochrome is able to exert such a powerful effect on growth and development. This new link between phytochrome and auxin may go some way to explain the extensive overlap in responses mediated by these two developmental regulators.     

The Cdc14B phosphatase contributes to ciliogenesis in zebrafish

Progression through the cell cycle relies on oscillation of cyclin-dependent kinase (Cdk) activity. One mechanism for downregulating Cdk signaling is to activate opposing phosphatases. The Cdc14 family of phosphatases counteracts Cdk1 phosphorylation in diverse organisms to allow proper exit from mitosis and cytokinesis. However, the role of the vertebrate CDC14 phosphatases, CDC14A and CDC14B, in re-setting the cell for interphase remains unclear. To understand Cdc14 function in vertebrates, we cloned the zebrafish cdc14b gene and used antisense morpholino oligonucleotides and an insertional mutation to inhibit its function during early development. Loss of Cdc14B function led to an array of phenotypes, including hydrocephaly, curved body, kidney cysts and left-right asymmetry defects, reminiscent of zebrafish mutants with defective cilia. Indeed, we report that motile and primary cilia were shorter in cdc14b-deficient embryos. We also demonstrate that Cdc14B function in ciliogenesis requires its phosphatase activity and can be dissociated from its function in cell cycle control. Finally, we propose that Cdc14B plays a role in the regulation of cilia length in a pathway independent of fibroblast growth factor (FGF). This first study of a loss of function of a Cdc14 family member in a vertebrate organism reveals a new role for Cdc14B in ciliogenesis and consequently in a number of developmental processes.     

Interactions between the cell cycle and embryonic patterning in Arabidopsis uncovered by a mutation in DNA polymerase epsilon

Pattern formation and morphogenesis require coordination of cell division rates and orientations with developmental signals that specify cell fate. A viable mutation in the TILTED1 locus, which encodes the catalytic subunit of DNA polymerase epsilon of Arabidopsis thaliana, causes a lengthening of the cell cycle by approximately 35% throughout embryo development and alters cell type patterning of the hypophyseal lineage in the root, leading to a displacement of the root pole from its normal position on top of the suspensor. Treatment of preglobular and early globular stages, but not later stage, embryos with the DNA polymerase inhibitor aphidicolin leads to a similar phenotype. The results uncover an interaction between the cell cycle and the processes that determine cell fate during plant embryogenesis.     

A cyclin-dependent protein kinase homologue associated with the basal body domains in the ciliate Tetrahymena thermophila

The tight coupling between cell cycle progression and morphogenetic development in the unicellular ciliates presents a unique model system for examination of the roles of Cdks in developmental processes. We here describe the isolation and characterization of the first cyclin-dependent kinase (Cdk) homologue, TtCdk1, from Tetrahymena thermophila. TtCdk1 corresponds to the larger of the two polypeptides recognized by anti-PSTAIRE antibody in a whole cell lysate, which differ from each other in their affinity for yeast p13(suc1) protein. In contrast to the constant protein expression levels of typical eukaryotic Cdks, the TtCdk1 protein level fluctuates periodically over the vegetative cell cycle, reaching a maximum at the end of the cell cycle, correlating with its histone H1 kinase activity. Its association with the membrane-skeletal domains that surround mature, but not nascent, basal bodies in the cell cortex suggests that TtCdk1 plays a role in the regulation of cortical morphogenesis in T. thermophila. A partial TtCDK1 knockout cell line constructed through somatic biolistic transformation resulted in a reduction of the regularity of the rows of basal bodies plus an additional effect on chromatin condensation in both macro- and micronuclei. Unlike the situations in higher eukaryotic cells, no apparent effect on basal body duplication was found upon disruption of the TtCDK1 gene.     

The Jak/STAT pathway in model organisms: emerging roles in cell movement

The JAK/STAT pathway was originally identified in mammals. Studies of this pathway in the mouse have revealed that JAK/STAT signaling plays a central role during hematopoeisis and other developmental processes. The role of JAK/STAT signaling in blood appears to be conserved throughout evolution, as it is also required during fly hematopoeisis. Studies in Dictyostelium, Drosophila, and zebrafish have shown that the JAK/STAT pathway is also required in an unusually broad set of developmental decisions, including cell proliferation, cell fate determination, cell migration, planar polarity, convergent extension, and immunity. There is increasing evidence that the versatility of this pathway relies on its cooperation with other signal transduction pathways. In this review, we discuss the components of the JAK/STAT pathway in model organisms and what is known about its requirement in cellular and developmental processes. In particular, we emphasize recent insights into the role that this pathway plays in the control of cell movement.