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1.  CREB and the CRTC co-activators: sensors for hormonal and metabolic signals 
The cyclic AMP-responsive element-binding protein (CREB) is phosphorylated in response to a wide variety of signals, yet target gene transcription is only increased in a subset of cases. Recent studies indicate that CREB functions in concert with a family of latent cytoplasmic co-activators called cAMP-regulated transcriptional co-activators (CRTCs), which are activated through dephosphorylation. A dual requirement for CREB phosphorylation and CRTC dephosphorylation is likely to explain how these activator–co-activator cognates discriminate between different stimuli. Following their activation, CREB and CRTCs mediate the effects of fasting and feeding signals on the expression of metabolic programmes in insulin-sensitive tissues.
doi:10.1038/nrm3072
PMCID: PMC4324555  PMID: 21346730
2.  Remodelling the extracellular matrix in development and disease 
The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.
doi:10.1038/nrm3904
PMCID: PMC4316204  PMID: 25415508
3.  [No title available] 
PMCID: PMC4060434  PMID: 24452469
4.  Illuminating cell signalling with optogenetic tools 
The light-based control of ion channels has been transformative for the neurosciences, but the optogenetic toolkit does not stop there. An expanding number of proteins and cellular functions have been shown to be controlled by light, and the practical considerations in deciding between reversible optogenetic systems (such as systems that use light-oxygen-voltage domains, phytochrome proteins, cryptochrome proteins and the fluorescent protein Dronpa) are well defined. The field is moving beyond proof of concept to answering real biological questions, such as how cell signalling is regulated in space and time, that were difficult or impossible to address with previous tools.
doi:10.1038/nrm3837
PMCID: PMC4145075  PMID: 25027655
5.  Capping Protein Regulators Fine-Tune Actin Assembly Dynamics 
Capping protein (CP) regulates actin polymerization by binding the barbed end of an actin filament, which blocks addition and loss of actin subunits. Recent structural and biochemical studies provide new insight into how cells control the actin capping activity of CP. Several molecules indirectly regulate CP by interacting with filament barbed ends and preventing binding of CP; others bind directly to CP and sterically block its interaction with an actin filament. A diverse and otherwise unrelated set of proteins contains a motif for CP regulation termed the “Capping Protein Interaction” (CPI) motif. These proteins bind directly to CP, recruit or target CP to a subcellular location, and modulate its actin-capping activity via allosteric effects.
doi:10.1038/nrm3869
PMCID: PMC4271544  PMID: 25207437
6.  Molecular mechanisms of epithelial–mesenchymal transition 
The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial–mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.
doi:10.1038/nrm3758
PMCID: PMC4240281  PMID: 24556840
7.  Abscission: Orchestration of vesicle transport, ESCRTs and kinase surveillance 
Preface
During the final stage of cell division, the future daughter cells are physically separated in a process called abscission. This process requires coordination of a number of molecular machines that mediate a complex series of events to culminate in the final separation of daughter cells. Abscission is coordinated with other cellular processes (for example, nuclear pore reassembly) through mitotic kinases that act as master regulators to ensure proper progression of abscission.
doi:10.1038/nrm3395
PMCID: PMC4215936  PMID: 22781903
8.  Organization and execution of the epithelial polarity programme 
Epithelial cells require apical–basal plasma membrane polarity to perform crucial vectorial transport functions and cytoplasmic polarity to generate different cell progenies for tissue morphogenesis. The establishment and maintenance of a polarized epithelial cell with apical, basolateral and ciliary surface domains is guided by an epithelial polarity programme (EPP) that is controlled by a network of protein and lipid regulators. The EPP is organized in response to extracellular cues and is executed through the establishment of an apical-basal axis, intercellular junctions, epithelial–specific cytoskeletal rearrangements and a polarized trafficking machinery. Recent studies have provided insight on the interactions of the EPP with the polarized trafficking machinery and how they regulate epithelial polarization and depolarization.
doi:10.1038/nrm3775
PMCID: PMC4211427  PMID: 24651541
9.  Computational morphodynamics of plants: integrating development over space and time 
Preface
The emerging field of computational morphodynamics aims to understand the changes that occur in space and time during development by combining three technical strategies: live imaging to observe development as it happens, image processing and analysis to extract quantitative information, and computational modelling to express and test time-dependent hypotheses. The strength of the field comes from the iterative and combined use of these techniques, which has provided important insight into plant development.
doi:10.1038/nrm3079
PMCID: PMC4128830  PMID: 21364682
10.  MicroRNAs: key regulators of stem cells 
The hallmark of a stem cell is its ability to self-renew and to produce numerous differentiated cells. This unique property is controlled by dynamic interplays between extrinsic signalling, epigenetic, transcriptional and post-transcriptional regulations. Recent research indicates that microRNAs (miRNAs) have an important role in regulating stem cell self-renewal and differentiation by repressing the translation of selected mRNAs in stem cells and differentiating daughter cells. Such a role has been shown in embryonic stem cells, germline stem cells and various somatic tissue stem cells. These findings reveal a new dimension of gene regulation in controlling stem cell fate and behaviour.
doi:10.1038/nrm2621
PMCID: PMC4118578  PMID: 19165214
11.  Talins and kindlins; partners in integrin-mediated adhesion 
Integrin receptors provide a dynamic tightly-regulated link between the extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signalling networks, enabling cells to sense and respond to their chemical and physical environment. Talins and kindlins, two families of FERM–domain proteins, bind the cytoplasmic tail of integrins, recruit cytoskeletal and signalling proteins involved in mechano-transduction, and synergise to activate integrin binding to extracellular ligands. New data reveal the domain structure of full-length talin, provide insights into talin-mediated integrin activation, and show that RIAM recruits talin to the plasma membrane while vinculin stabilises talin in cell–matrix junctions. How Kindlins’ act is less well defined, but disease-causing mutations show that kindlins are also essential for integrin activation, adhesion, cell spreading and signalling.
doi:10.1038/nrm3624
PMCID: PMC4116690  PMID: 23860236
12.  Group choreography: mechanisms orchestrating the collective movement of border cells 
Cell movements are essential for animal development and homeostasis but also contribute to disease. Moving cells typically extend protrusions towards a chemoattractant, adhere to the substrate, contract and detach at the rear. It is less clear how cells that migrate in interconnected groups in vivo coordinate their behaviour and navigate through natural environments. The border cells of the Drosophila melanogaster ovary have emerged as an excellent model for the study of collective cell movement, aided by innovative genetic, live imaging, and photomanipulation techniques. Here we provide an overview of the molecular choreography of border cells and its more general implications.
doi:10.1038/nrm3433
PMCID: PMC4099007  PMID: 23000794
13.  Metabolic requirements for the maintenance of self-renewing stem cells 
A distinctive feature of stem cells is their capacity to self-renew to maintain pluripotency. Studies of genetically-engineered mouse models and recent advances in metabolomic analysis, particularly in haematopoietic stem cells, have deepened our understanding of the contribution made by metabolic cues to the regulation of stem cell self-renewal. Many types of stem cells heavily rely on anaerobic glycolysis, and stem cell function is also regulated by bioenergetic signalling, the AKT–mTOR pathway, Gln metabolism and fatty acid metabolism. As maintenance of a stem cell pool requires a finely-tuned balance between self-renewal and differentiation, investigations into the molecular mechanisms and metabolic pathways underlying these decisions hold great therapeutic promise.
doi:10.1038/nrm3772
PMCID: PMC4095859  PMID: 24651542
14.  Emerging roles for chromatin as a signal integration and storage platform 
Cells of a multicellular organism, all containing nearly identical genetic information, respond to differentiation cues in variable ways. In addition, cells are plastic, able to execute their specialized function while maintaining the ability to adapt to environmental changes. This is achieved through multiple mechanisms, including the direct regulation of chromatin-based processes in response to stimuli. How signal transduction pathways directly communicate with chromatin to change the epigenetic landscape is poorly understood. The preponderance of covalent modifications on histone tails coupled with a relatively small number of functional outputs raises the possibility that chromatin acts as a site of signal integration and storage.
doi:10.1038/nrm3545
PMCID: PMC4082330  PMID: 23524488
15.  Post-translational modifications of intermediate filament proteins: mechanisms and functions 
Preface
Intermediate filaments (IFs) are cytoskeletal and nucleoskeletal structures that provide mechanical and stress-coping resilience to cells, contribute to subcellular and tissue-specific biological functions, and facilitate intracellular communication. IF proteins, including nuclear lamins and cytoplasmic keratins, vimentin, desmin, neurofilaments, and glial fibrillary acidic protein, undergo various functionally important post-translational modifications (PTMs). Proteomic advances highlight the enormous complexity of IF PTMs, which include phosphorylation, glycosylation, sumoylation, acetylation, and prenylation, as well as their ability to regulate IF proteins, and are likely to reveal novel modifications. We would like to keep the original statement, since the revised version seems to imply that proteomic advances provide insight into the ability of PTMs to regulate IF proteins, which is not the case. Future studies will need to characterize their on–off mechanisms, cross-talk, and utility as biomarkers and targets for diseases involving the IF cytoskeleton.
doi:10.1038/nrm3753
PMCID: PMC4079540  PMID: 24556839
16.  Organization of the ER–Golgi interface for membrane traffic control 
Coat protein complex I (COPI) and COPII are required for bidirectional membrane trafficking between the endoplasmic reticulum (ER) and the Golgi. While these core coat machineries and other transport factors are highly conserved across species, high-resolution imaging studies indicate that the organization of the ER–Golgi interface is varied in eukaryotic cells. Regulation of COPII assembly, in some cases to manage distinct cellular cargo, is emerging as one important component in determining this structure. Comparison of the ER–Golgi interface across different systems, particularly mammalian and plant cells, reveals fundamental elements and distinct organization of this interface. A better understanding of how these interfaces are regulated to meet varying cellular secretory demands should provide key insights into the mechanisms that control efficient trafficking of proteins and lipids through the secretory pathway.
doi:10.1038/nrm3588
PMCID: PMC4064004  PMID: 23698585
17.  Peroxisomes take shape 
Peroxisomes carry out various oxidative reactions that are tightly regulated to adapt to the changing needs of the cell and varying external environments. Accordingly, they are remarkably fluid and can change dramatically in abundance, size, shape and content in response to numerous cues. These dynamics are controlled by multiple aspects of peroxisome biogenesis that are coordinately regulated with each other and with other cellular processes. Ongoing studies are deciphering the diverse molecular mechanisms that underlie biogenesis and how they cooperate to dynamically control peroxisome utility. These important challenges should lead to an understanding of peroxisome dynamics that can be capitalized upon for bioengineering and the development of therapies to improve human health.
doi:10.1038/nrm3700
PMCID: PMC4060825  PMID: 24263361
18.  Dynamic niches in the origination and differentiation of haematopoietic stem cells 
Haematopoietic stem cells (HSCs) are multipotent, self-renewing progenitors that generate all mature blood cells. HSC function is tightly controlled to maintain haematopoietic homeostasis, and this regulation relies on specialized cells and factors that constitute the haematopoietic ‘niche’, or microenvironment. Recent discoveries, aided in part by technological advances in in vivo imaging, have engendered a new appreciation for the dynamic nature of the niche, identifying novel cellular and acellular niche components and uncovering fluctuations in the relative importance of these components over time. These new insights significantly improve our understanding of haematopoiesis and raise fundamental questions about what truly constitutes a stem cell niche.
doi:10.1038/nrm3184
PMCID: PMC4040463  PMID: 21886187
19.  TETonic shift: biological roles of TET proteins in DNA demethylation and transcription 
In many organisms, the methylation of cytosine in DNA has a key role in silencing ‘parasitic’ DNA elements, regulating transcription and establishing cellular identity. The recent discovery that ten-eleven translocation (TET) proteins are 5-methylcytosine oxidases has provided several chemically plausible pathways for the reversal of DNA methylation, thus triggering a paradigm shift in our understanding of how changes in DNA methylation are coupled to cell differentiation, embryonic development and cancer.
doi:10.1038/nrm3589
PMCID: PMC3804139  PMID: 23698584
20.  Origins and implications of pluripotent stem cell variability and heterogeneity 
Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in their capacity to differentiate into desired cell types in vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could ‘lock’ the pluripotency network resulting in residual pluripotent cells or alter the signalling response of developmental pathways leading to lineage bias. The molecular contributors to functional variability and heterogeneity in both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are only beginning to emerge, yet they are crucial to the future of the stem cell field.
doi:10.1038/nrm3584
PMCID: PMC3980962  PMID: 23673969
21.  Specialized ribosomes: a new frontier in gene regulation and organismal biology 
Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than intrinsic regulatory capacity in mRNA translation. However, emerging studies reveal that ribosome activity may be highly regulated. Heterogeneity in ribosome composition resulting from differential expression and post-translational modifications of ribosomal proteins, ribosomal RNA (rRNA) diversity and the activity of ribosome-associated factors may generate ‘specialized ribosomes’ that have a substantial impact on how the genomic template is translated into functional proteins. Moreover, constitutive components of the ribosome may also exert more specialized activities by virtue of their interactions with specific mRNA regulatory elements such as internal ribosome entry sites (IRESs) or upstream open reading frames (uORFs). Here we discuss the hypothesis that intrinsic regulation by the ribosome acts to selectively translate subsets of mRNAs harbouring unique cis-regulatory elements, thereby introducing an additional level of regulation in gene expression and the life of an organism.
doi:10.1038/nrm3359
PMCID: PMC4039366  PMID: 22617470
22.  Synthetic biology in mammalian cells: Next generation research tools and therapeutics 
Recent progress in DNA manipulation and gene circuit engineering has greatly improved our ability to programme and probe mammalian cell behaviour. These advances have led to a new generation of synthetic biology research tools and potential therapeutic applications. Programmable DNA-binding domains and RNA regulators are leading to unprecedented control of gene expression and elucidation of gene function. Rebuilding complex biological circuits such as T cell receptor signalling in isolation from their natural context has deepened our understanding of network motifs and signalling pathways. Synthetic biology is also leading to innovative therapeutic interventions based on cell-based therapies, protein drugs, vaccines and gene therapies.
doi:10.1038/nrm3738
PMCID: PMC4032074  PMID: 24434884
23.  TGFβ signalling in context 
The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.
doi:10.1038/nrm3434
PMCID: PMC4027049  PMID: 22992590
24.  MicroRNAs in Metabolism and Metabolic Disorders 
MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and b play a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the SREBP transcription factors. Metabolic miRNAs such as miR-103 and miR-107 regulate insulin and glucose homeostasis, while others, such as miR-34a, may be key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets to ameliorate cardiometabolic disorders.
doi:10.1038/nrm3313
PMCID: PMC4021399  PMID: 22436747
25.  Re-starting life: Fertilization and the transition from meiosis to mitosis 
Fertilization triggers a complex cellular programme that transforms two highly specialized meiotic germ cells, the oocyte and the sperm, into a totipotent mitotic embryo: linkages between sister chromatids are remodelled to support the switch from reductional meiotic to equational mitotic divisions; the centrosome, which is absent from the egg, needs to be reintroduced; the axis of cell division is shifted from extremely asymmetric to symmetric; genomic imprinting is selectively erased and re-established; and protein expression shifts from translational control back to transcriptional control. Recent work has started to reveal how this remarkable transition from meiosis to mitosis is achieved.
doi:10.1038/nrm3643
PMCID: PMC4021448  PMID: 23942453

Results 1-25 (163)