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Key Points Microtubule organization and dynamics are controlled by proteins that associate with the two microtubule extremities, the plus end and the minus end. Proteins accumulating at microtubule ends can promote or inhibit microtubule polymerization, enhance or block microtubule disassembly, or induce transitions between microtubule growth and shortening. Microtubule plus-end-tracking proteins (+TIPs) can accumulate at microtubule ends by recognizing the stabilizing GTP cap at growing microtubule tips or the curvature of the outermost part of the microtubule, or by plus-end-directed motor activity. This accumulation can be enhanced by electrostatic interactions between positively charged protein domains and the negatively charged microtubule lattice. +TIPs form extensive interaction networks, which depend on a limited number of protein motifs and modules that bind to each other with moderate affinity, allowing rapid remodelling of the end-associated complexes during microtubule growth and shortening. The recruitment of proteins with SxIP and cytoskeleton-associated protein Gly-rich (CAP-Gly) domains by the 'autonomous' +TIPs of the end-binding protein (EB) family plays a major part in the formation of these networks. +TIP networks are responsible for a large range of cellular functions, such as microtubule guidance along other cytoskeletal elements, microtubule attachment to the cell cortex, kinetochores and intracellular membrane organelles, positioning of microtubule arrays and signalling. Microtubule minus-end-targeting proteins (−TIPs) of the calmodulin-regulated spectrin-associated protein (CAMSAP) and Patronin family accumulate at free, growing microtubule minus ends and control the architecture of microtubule networks by stabilizing non-centrosomal microtubules. A wide range of diverse pharmacological agents can target microtubule tips either directly or indirectly and cooperate with +TIPs in regulating the dynamics of microtubule ends. Microtubule plus ends and minus ends accumulate specific sets of proteins that can regulate microtubule dynamics, connect microtubules to cellular structures and recruit signalling molecules that collectively control cellular behaviour. Our knowledge of the factors that associate with microtubule ends, and the mechanisms through which they do this, has strongly increased in recent years. Microtubules have fundamental roles in many essential biological processes, including cell division and intracellular transport. They assemble and disassemble from their two ends, denoted the plus end and the minus end. Significant advances have been made in our understanding of microtubule plus-end-tracking proteins (+TIPs) such as end-binding protein 1 (EB1), XMAP215, selected kinesins and dynein. By contrast, information on microtubule minus-end-targeting proteins (−TIPs), such as the calmodulin-regulated spectrin-associated proteins (CAMSAPs) and Patronin, has only recently started to emerge. Here, we review our current knowledge of factors, including microtubule-targeting agents, that associate with microtubule ends to control the dynamics and function of microtubules during the cell cycle and development.

In the leaf epidermis, stomatal pores allow gas exchange between plants and the environment. The production of stomatal guard cells requires the lineage cells to divide asymmetrically. In this Insight review, we describe an emerging picture of how intrinsic molecules drive stomatal asymmetric cell division in multidimensions, from transcriptional activities in the nucleus to the dynamic assembly of the polarity complex at the cell cortex. Given the significant roles of stomatal activity in plant responses to environmental changes, we incorporate recent advances in external cues feeding into the regulation of core molecular machinery required for stomatal development. The work we discuss here is mainly based on the dicot plant Arabidopsis thaliana with summaries of recent progress in the monocots.

Key Points Mitochondria are organelles with key roles in cellular metabolism. They have unique cellular dynamics to ensure their proper distribution to dividing cells and high fidelity of inheritance of their genome in a maternal mode of transmission. In mammals, mitochondrial segregation during cell division seems to be primarily a passive process. Mitochondrial fusion, fission, transport, contacts with the endoplasmic reticulum and mitophagy all play a part in maintaining a homogeneous population that is spatially well distributed in the cell soma and that can thus be partitioned equally to daughter cells. Mitochondrial DNA (mtDNA) inheritance from one generation to another is strongly influenced by mtDNA bottlenecks and genetic selection that occur during oogenesis and early embryonic development. Quality-control mechanisms are probably present to minimize the accumulation of pathogenic mutations, which lead to a class of diseases termed mitochondrial encephalomyopathies. The depletion of paternal mitochondria during fertilization is nearly universal in metozoans, although its timing and mechanisms vary substantially between species. Proteasome-dependent degradation, mtDNA degradation and mitophagy have been implicated in this process in different organisms. Mitochondria contain a genome that is inherited maternally; this complicates their segregation during cell division, oogenesis and development. Mechanisms that ensure mitochondrial integrity include fusion and fission processes, organelle transport, mitophagy and genetic selection. Defects in these processes can lead to cell and tissue pathologies. During cell division, it is critical to properly partition functional sets of organelles to each daughter cell. The partitioning of mitochondria shares some common features with that of other organelles, particularly in the use of interactions with cytoskeletal elements to facilitate delivery to the daughter cells. However, mitochondria have unique features — including their own genome and a maternal mode of germline transmission — that place additional demands on this process. Consequently, mechanisms have evolved to regulate mitochondrial segregation during cell division, oogenesis, fertilization and tissue development, as well as to ensure the integrity of these organelles and their DNA, including fusion–fission dynamics, organelle transport, mitophagy and genetic selection of functional genomes. Defects in these processes can lead to cell and tissue pathologies.

Epithelial tissues require the removal and replacement of damaged cells to sustain a functional barrier. Dying cells provide instructive cues that can influence surrounding cells to proliferate, but how these signals are transmitted to their healthy neighbors to control cellular behaviors during tissue homeostasis remains poorly understood. Here we show that dying stem cells facilitate communication with adjacent stem cells by caspase-dependent production of Wnt8a-containing apoptotic bodies to drive cellular turnover in living epithelia. Basal stem cells engulf apoptotic bodies, activate Wnt signaling, and are stimulated to divide to maintain tissue-wide cell numbers. Inhibition of either cell death or Wnt signaling eliminated the apoptosis-induced cell division, while overexpression of Wnt8a signaling combined with induced cell death led to an expansion of the stem cell population. We conclude that ingestion of apoptotic bodies represents a regulatory mechanism linking death and division to maintain overall stem cell numbers and epithelial tissue homeostasis. Damaged epithelial tissues are known to compensate for cell death through compensatory cell divisions to maintain epithelial integrity. Here, the authors show in living epithelia that dying cells stimulate adjacent stem cells to divide through caspase-dependent production of Wnt8a-containing apoptotic bodies.

The quiescent center (QC) plays an essential role during root development by creating a microenvironment that preserves the stem cell fate of its surrounding cells. Despite being surrounded by highly mitotic active cells, QC cells self-renew at a low proliferation rate. Here, we identified the ERF115 transcription factor as a rate-limiting factor of QC cell division, acting as a transcriptional activator of the phytosulfokine PSK5 peptide hormone. ERF115 marks QC cell division but is restrained through proteolysis by the APC/C CCS52A2 ubiquitin ligase, whereas QC proliferation is driven by brassinosteroid-dependent ERF115 expression. Together, these two antagonistic mechanisms delimit ERF115 activity, which is called upon when surrounding stem cells are damaged, revealing a cell cycle regulatory mechanism accounting for stem cell niche longevity.

Environmental fluctuations affect distribution, growth and abundance of diatoms in nature, with iron (Fe) availability playing a central role. Studies on the response of diatoms to low Fe have either utilized continuous (24 hr) illumination or sampled a single time of day, missing any temporal dynamics. We profiled the physiology, metabolite composition, and global transcripts of the pennate diatom Phaeodactylum tricornutum during steady-state growth at low, intermediate, and high levels of dissolved Fe over light:dark cycles, to better understand fundamental aspects of genetic control of physiological acclimation to growth under Fe-limitation. We greatly expand the catalog of genes involved in the low Fe response, highlighting the importance of intracellular trafficking in Fe-limited diatoms. P. tricornutum exhibited transcriptomic hallmarks of slowed growth leading to prolonged periods of cell division/silica deposition, which could impact biogeochemical carbon sequestration in Fe-limited regions. Light harvesting and ribosome biogenesis transcripts were generally reduced under low Fe while transcript levels for genes putatively involved in the acquisition and recycling of Fe were increased. We also noted shifts in expression towards increased synthesis and catabolism of branched chain amino acids in P. tricornutum grown at low Fe whereas expression of genes involved in central core metabolism were relatively unaffected, indicating that essential cellular function is protected. Beyond the response of P. tricornutum to low Fe, we observed major coordinated shifts in transcript control of primary and intermediate metabolism over light:dark cycles which contribute to a new view of the significance of distinctive diatom pathways, such as mitochondrial glycolysis and the ornithine-urea cycle. This study provides new insight into transcriptional modulation of diatom physiology and metabolism across light:dark cycles in response to Fe availability, providing mechanistic understanding for the ability of diatoms to remain metabolically poised to respond quickly to Fe input and revealing strategies underlying their ecological success.

Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition—G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell’s target size. Animal cells come in many different sizes. In humans, for example, egg cells are thousands of times larger than sperm cells. Yet cells of any given type are often strikingly similar in size. The cells that line the surface of organs including the skin and kidneys are especially uniform; in fact a loss of size uniformity in certain tumors is a sign of malignancy. What kind of regulation could enable separate cells within a tissue to have the same size? One possibility is that each type of cell is programmed with a specific target size, and that a cell can sense if it strays from its target and take steps to compensate. Animal cells sensing their own size was first reported in the 1960s, and now Ginzberg et al. confirm that human cells grown in the laboratory do indeed monitor their size and correct deviations from their target. It turns out that two separate and independent processes help to keep all the cells in the population roughly uniform in size. Firstly, proliferating human cells that are smaller than their target size spend longer growing before they divide. Secondly, at two time points between cell divisions, large cells adjust their growth rate such that they grow slower than small cells. To show these processes in action, Ginzberg et al. introduced mutations or chemicals that perturbed the length of time between cell divisions or the rate of a cell’s growth. As expected, most of these perturbations had only a modest influence on cell size, due to the cell’s compensatory strategies. Cells that had less time to grow compensated by more quickly making new protein molecules, meaning that they still had enough material to build two new cells by the time they had to divide. In contrast, if a cell’s division was artificially delayed, it reduced its growth rate to stop it from becoming too large. Similarly, cells grown in conditions that slow the production of proteins extended the time between their cell divisions to give them enough time to accumulate the material required for two new cells. In a recent related study, Liu, Ginzberg et al. identified some of the molecules that a human cell uses to sense its own size. Together these two studies now pave the road to answering a fundamental question in cell biology: what is the elusive cell size sensor? Understanding how cells sense their size will open a window onto how quantitative information is programmed, sensed and communicated within living cells. These findings will shed also new light onto how cells specialize into cell types of different sizes, and what happens when cells lose the ability to sense or regulate their size in diseases like cancers.

In plants, postembryonic formation of new organs helps shape the adult organism. This requires the tight regulation of when and where a new organ is formed and a coordination of the underlying cell divisions. To build a root system, new lateral roots are continuously developing, and this process requires the tight coordination of asymmetric cell division in adjacent pericycle cells. We identified EXPANSIN A1 (EXPA1) as a cell wall modifying enzyme controlling the divisions marking lateral root initiation. Loss of EXPA1 leads to defects in the first asymmetric pericycle cell divisions and the radial swelling of the pericycle during auxin-driven lateral root formation. We conclude that a localized radial expansion of adjacent pericycle cells is required to position the asymmetric cell divisions and generate a core of small daughter cells, which is a prerequisite for lateral root organogenesis.

Dystrophin is expressed in muscle stem cells, in which it regulates their cell division and proper repopulation. Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.