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Volume is a fundamental morphological feature of cells, influencing a wide variety of cellular processes. Because it is coupled to so many processes, cells employ regulatory mechanisms to ensure cells exhibit a limited range of sizes. Recent work in budding yeast has shown that a key cell cycle regulator, the G1/S transcriptional inhibitor Whi5, is synthesized independent of cell size. The dilution of Whi5 in larger cells links cell size to G1/S cell cycle progression. However, it has also been shown that growth over the full cell cycle does not depend on cell size at birth, termed an "adder". It has been proposed that this observation suggests that cell size is controlled over the course of the full cell cycle, leading to an apparent contradiction. Here we show that cell size control occurs independently in different parts of the cell cycle and does not reflect a molecular mechanism measuring growth during the full cell cycle. Consistent with previous results, we find that cell size sets the rate of entry into the cell cycle during the pre-Start period. We also identify the key parameters predicting the rate of entry into cytokinesis at the end of the post-Start period. We use these parameters to build a phenomenological cell cycle model that recapitulates observations of growth and size distributions for cells without explicit coupling between cell cycle phases. Our model predicts that changes to the rate of progression through either phase of the cell cycle should disrupt the adder behavior and we show that mutants in genes controlling G1/S size control breaks the adder. The rate of passage through Start depends on volume, which is thought to depend on the size-independent expression of Whi5. This type of gene expression scaling is unusual because although cells of a given type may span a range of sizes, most proteins and RNA are maintained at constant, size independent, concentrations, rather than amounts. This ensures that biochemical reactions proceed independently of cell size. The identification of WHI5, whose gene product differs from this pattern, raises two fundamental questions: (1) Are there additional genes whose synthesis is decoupled from cell volume? (2) If most gene expression is proportional to cell size, what molecular mechanism promotes cell-size-independent gene expression? To address these questions, we analyzed flow cytometry data collected using the yeast GFP-fusion library. We identified approximately 200 genes whose expression is not proportional to cell volume. Gene ontology analysis revealed that non-scaling genes are enriched for genes with roles in DNA-templated processes and membrane transport. This suggests that cells employ differential protein synthesis to coordinate protein requirements with the scaling properties of cellular structures. Membranes are expected to scale as size2/3 and DNA content is independent of size. To understand the mechanisms that underlie size-independent gene expression, we used transcriptional reporters of non-scaling genes, including WHI5, and determined that cell-size-independent regulation of some genes is due to non-scaling transcription rates. Targeted analysis of the WHI5 promoter showed that the region between 1000 bases and 550 bases upstream of the translation start site are required for cell-size-independent gene expression. This suggests there is a molecular element within this region required for non-scaling gene expression. Finally, we identify a partitioning mechanism ensuring proteins are partitioned in dividing cells in amounts that are independent of asymmetric sizes of the mother and daughter cells. Tight chromatin association ensures that proteins are segregated in equal amounts despite asymmetric division. Consistent with this model, while Whi5 is normally partitioned in equal amounts, a Whi5 protein that lacks the domain required for association with transcription factors is partitioned in proportion to the mother-daughter cell size ratio. Taken together, our work demonstrates a functional role for differential size-dependency of protein synthesis and gives insights into the underlying molecular mechanism(s).
Although questions on cell size have been investigated for more than half a century, molecular mechanisms that 'program' the size of animal cells are only starting to be revealed. My Ph.D. research focuses on the molecular mechanisms that promote cell size uniformity in proliferating mammalian cells. By relying on a high-content small chemical screen, I identified candidate proteins and signaling molecules that may function as cell size specifiers. Intriguingly, analysis of the screen hits suggested a role for the p38 MAPK in the long-sought mammalian cell size checkpoint. In follow-up experiments, I showed that p38 MAPK signaling is activated in small, but not large cells, which selectively inhibits the progression of small cells into S phase. Consistent with this model, chemical and genetic perturbations of p38 resulted in the loss of the compensatory G1 length extension in small cells; cells lacking p38 activity proliferated faster, were smaller in size and displayed increased size heterogeneity. Altogether, my work suggests that the p38 MAPK pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity. In this thesis, I first present an in-depth review of the animal cell size research. Reflecting on literature, I summarize in Chapter 1.1 a convergence of historical and recent evidence that support size sensing as a cell-autonomous function of individual animal cells. I also discuss the historical debates on animal cell size sensing and offer my understanding of how these "conflicting" literature may be resolved through new interpretations. In Chapter 1.2, I discuss in detail how cell size affects cellular, tissue and organismal level functions. I hope this inspires more functional and mechanistic research on cell size in the future. In the last Chapter, I further discuss the implications of the p38 signaling and cell size control and introduce in brief the branches of follow-up research that emerged from my thesis work.
The I. Beritashvili Center of Experimental Biomedicine was established in 2010 on the basis of merging four well-known Georgian research institutes. They are: The I. Beritashvili Institute of Physiology, one of the most prominent research centers of Georgia, where basic and applied research in different fields of neurophysiology has been conducted since 1935; the Institute of Molecular Biology and Biophysics; the Center for Radiology and Radiation Ecology, which for many years operated as departments at the I. Beritashvili Institute of Physiology; and one of the leading research centers for Georgia: The Center of Experimental Neurology.This edited book is the second volume containing chapters constituting the research priorities of the I. Beritashvili Center of Experimental Biomedicine and covers the experimental study of fundamental issues in the functioning of physiological (mainly, neurophysiological) mechanisms during normal and pathological conditions. The first book - Cellular and Molecular Mechanisms of Physiological Functions and Their Disorders - published by Nova Science Publishers Inc. in 2015, was also devoted to the same general problems.In the present edited book, particular attention is drawn to the study of extremely important processes underlying the basic mechanisms and disorders of various phenomenon of integrative activity of the brain: General behavior, learning and memory processes, the sleep-wakefulness cycle, regulation of adequate blood supply, hormesis, vision, depression, experimental comatose state, epilepsy, tumor diseases, pain and analgesia, the state of anxiety and aggression. All of the mentioned processes are studied on the molecular, cellular and systemic levels of their organization. It has to be noted herewith that each chapter within the collection of works represents the results of separate, independent studies implemented by different scientific departments of the Center; therefore, the chapters are not directly related to each other and have been arranged alphabetically based on the surnames of the authors. The authors would like to take this opportunity and present to the reader the scientific and institutional infrastructure of the Center, which consists of departments and laboratories.Nowadays, the Center is comprised of seven departments: Neurophysiology, Membranology, Biochemistry, Blood Circulation and Metabolism, Neurotoxicology, Biophysics and Radiobiology and nine laboratories: Behavior and Cognitive Functions, Physiology of Vision, Neurobiology of Sleep-Wakefulness Cycle, Ultra- and Nanoarchitectonics of the Brain, Experimental Neurology, Pain and Analgesia, Bioinformatics, Structure and Function of Genomes, and the Problems of Radiation Safety.In addition to bilateral scientific cooperation with many famous European and American scientific institutions, the Center is a member of the International Science Consortium "From Molecular to Cellular Events in Human Pathologies", of which the 2015 Annual Meeting was held in Tbilisi.The authors are sure that readers are fully aware of the theoretical and practical importance of the research related to problems of systemic, cellular and molecular mechanisms of physiological functions and their disorders. The presented collection of works contains the results of relevant research conducted over the last three years (2015-2018).The authors will be very grateful for any feedback, recommendations and suggestions regarding their research for the implementation of which they have invested a lot of effort, time, knowledge and experience.
Recent breakthroughs in the field of cell growth, particularly in the control of cell size, are reviewed by experts in the three major divisions of the field: growth of individual cells, growth of organs, and regulation of cell growth in the contexts of development and cell division. This book is an introductory overview of the field and should be adaptable as a textbook.
This volume presents a unique compilation of reviews on cell volume regulation in health and disease, with contributions from leading experts in the field. The topics covered include mechanisms and signaling of cell volume regulation and the effect of cell volume on cell function, with special emphasis on ion channels and transporters, kinases and gene expression. Several chapters elaborate on how cell volume regulatory mechanisms participate in the regulation of epithelial transport, urinary concentration, metabolism, migration, cell proliferation and apoptosis. Last but not least, this publication is an excellent guide to the role of cell volume in the pathophysiology of hypercatabolism, diabetes mellitus, brain edema, hemoglobinopathies, tumor growth and metastasis, to name just a few. Providing deeper insights into an exciting area of research which is also of clinical relevance, this publication is a valuable addition to the library of those interested in cell volume regulation.
A Top 25 CHOICE 2016 Title, and recipient of the CHOICE Outstanding Academic Title (OAT) Award. How much energy is released in ATP hydrolysis? How many mRNAs are in a cell? How genetically similar are two random people? What is faster, transcription or translation?Cell Biology by the Numbers explores these questions and dozens of others provid
With the invitation to edit this volume, I wanted to take the opportunity to assemble reviews on different aspects of circadian clocks and rhythms. Although most c- tributions in this volume focus on mammalian circadian clocks, the historical int- duction and comparative clocks section illustrate the importance of various other organisms in deciphering the mechanisms and principles of circadian biology. Circadian rhythms have been studied for centuries, but only recently, a mole- lar understanding of this process has emerged. This has taken research on circadian clocks from mystic phenomenology to a mechanistic level; chains of molecular events can describe phenomena with remarkable accuracy. Nevertheless, current models of the functioning of circadian clocks are still rudimentary. This is not due to the faultiness of discovered mechanisms, but due to the lack of undiscovered processes involved in contributing to circadian rhythmicity. We know for example, that the general circadian mechanism is not regulated equally in all tissues of m- mals. Hence, a lot still needs to be discovered to get a full understanding of cir- dian rhythms at the systems level. In this respect, technology has advanced at high speed in the last years and provided us with data illustrating the sheer complexity of regulation of physiological processes in organisms. To handle this information, computer aided integration of the results is of utmost importance in order to d- cover novel concepts that ultimately need to be tested experimentally.
The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life. Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration. This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system. It offers a complete and updated view of magnesiums involvement in central nervous system function and in so doing, brings together two main pillars of contemporary neuroscience research, namely providing an explanation for the molecular mechanisms involved in brain function, and emphasizing the connections between the molecular changes and behavior. It is the untiring efforts of those magnesium researchers who have dedicated their lives to unraveling the mysteries of magnesiums role in biological systems that has inspired the collation of this volume of work.