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issn:1943-0.64
1.  Erratum: Translational Control in Cancer Etiology 
doi:10.1101/cshperspect.a015891
PMCID: PMC3536345
2.  Protein Folding and Quality Control in the ER 
doi:10.1101/cshperspect.a015438
PMCID: PMC3405861  PMID: 22855729
3.  PRINCIPLES AND CONCEPTS OF DNA REPLICATION IN BACTERIA AND EUKARYA 
Cold Spring Harbor perspectives in biology  2013;5(7):10.1101/cshperspect.a010108 a010108.
The accurate copying of genetic information in the double helix of DNA is essential for inheritance of traits that define the phenotype of cells and the organism. The core machineries that copy DNA are conserved in all three domains of life, bacteria, archaea and eukaryotes. This introductory chapter outlines the general nature of the DNA replication machinery, but also points out important and key differences. The most complex organisms, eukaryotes, have to coordinate the initiation of DNA replication from many origins in each genome and impose regulation that maintains genomic integrity, not only for the sake of each cell, but for the organism as a whole. In addition, DNA replication in eukaryotes needs to be coordinated with inheritance of chromatin, developmental patterning of tissues and with cell division to ensure that the genome replicates once per cell division cycle.
doi:10.1101/cshperspect.a010108
PMCID: PMC3685895  PMID: 23818497
4.  Wnt Signaling and Forebrain Development 
Components of the Wnt signaling pathway are expressed in a tightly regulated and spatially specific manner during development of the forebrain, and Wnts are key regulators of regional forebrain identity. Wnt signaling from the cortical hem regulates the expansion and cell-type specification of the adjacent neuroepithelium and, in conjunction with Bmp, Fgf, and Shh signaling, controls dorsal–ventral forebrain patterning. Subsequently, Wnt signaling dynamically regulates the behavior of cortical progenitor cells, initially promoting the expansion of radial glia progenitor cells and later inducing neurogenesis by promoting terminal differentiation of intermediate progenitor cells. A role for Wnt signaling in cell-type specification has also been proposed.
Wnt signaling from the cortical hem regulates regional identity in the early forebrain. Later, Wnt signaling dynamically regulates the behavior of cortical progenitor cells.
doi:10.1101/cshperspect.a008094
PMCID: PMC3385962  PMID: 22621768
5.  The Elongation, Termination, and Recycling Phases of Translation in Eukaryotes 
This work summarizes our current understanding of the elongation and termination/recycling phases of eukaryotic protein synthesis. We focus here on recent advances in the field. In addition to an overview of translation elongation, we discuss unique aspects of eukaryotic translation elongation including eEF1 recycling, eEF2 modification, and eEF3 and eIF5A function. Likewise, we highlight the function of the eukaryotic release factors eRF1 and eRF3 in translation termination, and the functions of ABCE1/Rli1, the Dom34:Hbs1 complex, and Ligatin (eIF2D) in ribosome recycling. Finally, we present some of the key questions in translation elongation, termination, and recycling that remain to be answered.
Eukaryotes have unique features of translation elongation (e.g., eEF1 recycling, eEF2 modification, and eIF5A function), termination (e.g., the use of eRF1 and eRF3), and ribosome recycling.
doi:10.1101/cshperspect.a013706
PMCID: PMC3385960  PMID: 22751155
6.  Short-Term Presynaptic Plasticity 
Different types of synapses are specialized to interpret spike trains in their own way by virtue of the complement of short-term synaptic plasticity mechanisms they possess. Numerous types of short-term, use-dependent synaptic plasticity regulate neurotransmitter release. Short-term depression is prominent after a single conditioning stimulus and recovers in seconds. Sustained presynaptic activation can result in more profound depression that recovers more slowly. An enhancement of release known as facilitation is prominent after single conditioning stimuli and lasts for hundreds of milliseconds. Finally, tetanic activation can enhance synaptic strength for tens of seconds to minutes through processes known as augmentation and posttetantic potentiation. Progress in clarifying the properties, mechanisms, and functional roles of these forms of short-term plasticity is reviewed here.
Use-dependent presynaptic plasticity lasting tens of milliseconds to minutes can be divided into these major categories: depression, facilitation, and augmentation/posttetanic potentiation.
doi:10.1101/cshperspect.a005702
PMCID: PMC3385958  PMID: 22751149
7.  From Cis-Regulatory Elements to Complex RNPs and Back 
Messenger RNAs (mRNAs), the templates for translation, have evolved to harbor abundant cis-acting sequences that affect their posttranscriptional fates. These elements are frequently located in the untranslated regions and serve as binding sites for trans-acting factors, RNA-binding proteins, and/or small non-coding RNAs. This article provides a systematic synopsis of cis-acting elements, trans-acting factors, and the mechanisms by which they affect translation. It also highlights recent technical advances that have ushered in the era of transcriptome-wide studies of the ribonucleoprotein complexes formed by mRNAs and their trans-acting factors.
mRNAs harbor abundant cis-acting elements that direct the assembly of ribonucleoprotein particles (mRNPs), which influence their posttranscriptional fate.
doi:10.1101/cshperspect.a012245
PMCID: PMC3385959  PMID: 22751153
8.  Development and Homeostasis of the Skin Epidermis 
The skin epidermis is a stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections. The epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behavior. The epidermis undergoes a constant turnover and distinct stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments. Deregulation of the signaling pathways controlling the balance between renewal and differentiation often leads to cancer formation.
In the skin, at least three types of stem cells are responsible for maintaining different epidermal compartments. Distinct signaling pathways control their functions; deregulation of these pathways may lead to cancer.
doi:10.1101/cshperspect.a008383
PMCID: PMC3385954  PMID: 22751151
9.  On How Mammary Gland Reprogramming Metalloproteinases Couple Form with Function 
Metalloproteinases in extracellular proteolytic pathways are critical to mammary gland biology and tumorigenesis. However, intracellular and membrane proteases (e.g., caspases and cathepsins) may also play important roles.
doi:10.1101/cshperspect.a013474
PMCID: PMC3385951  PMID: 22661591
10.  On Using Functional Genetics to Understand Breast Cancer Biology 
Translating functional genomics screens into therapeutic interventions for treating breast cancer has presented challenges. Identifying synthetic lethal interactions in cancer cells using these screens may hold promise.
doi:10.1101/cshperspect.a013516
PMCID: PMC3385952  PMID: 22751154
11.  Genomic Imprinting and Epigenetic Control of Development 
Epigenetic mechanisms are extensively utilized during mammalian development. Specific patterns of gene expression are established during cell fate decisions, maintained as differentiation progresses, and often augmented as more specialized cell types are required. Much of what is known about these mechanisms comes from the study of two distinct epigenetic phenomena: genomic imprinting and X-chromosome inactivation. In the case of genomic imprinting, alleles are expressed in a parent-of-origin-dependent manner, whereas X-chromosome inactivation in females requires that only one X chromosome is active in each somatic nucleus. As model systems for epigenetic regulation, genomic imprinting and X-chromosome inactivation have identified and elucidated the numerous regulatory mechanisms that function throughout the genome during development.
Genomic imprinting (e.g., at the Igf2/H19 locus) and X-chromosome inactivation have illuminated regulatory mechanisms that function throughout the genome during development.
doi:10.1101/cshperspect.a008136
PMCID: PMC3385953  PMID: 22687277
12.  The RNA Worlds in Context 
There are two RNA worlds. The first is the primordial RNA world, a hypothetical era when RNA served as both information and function, both genotype and phenotype. The second RNA world is that of today's biological systems, where RNA plays active roles in catalyzing biochemical reactions, in translating mRNA into proteins, in regulating gene expression, and in the constant battle between infectious agents trying to subvert host defense systems and host cells protecting themselves from infection. This second RNA world is not at all hypothetical, and although we do not have all the answers about how it works, we have the tools to continue our interrogation of this world and refine our understanding. The fun comes when we try to use our secure knowledge of the modern RNA world to infer what the primordial RNA world might have looked like.
Studying the numerous roles of RNA today—from catalysis and translation to gene regulation and host defense—may help us infer what the primordial RNA world looked like four billion years ago.
doi:10.1101/cshperspect.a006742
PMCID: PMC3385955  PMID: 21441585
13.  Signaling in Control of Cell Growth and Metabolism 
Mammalian cells require growth-factor-receptor-initiated signaling to proliferate. Signal transduction not only initiates entry into the cell cycle, but also reprograms cellular metabolism. This instructional metabolic reprogramming is critical if the cell is to fulfill the anabolic and energetic requirements that accompany cell growth and division. Growth factor signaling mediated by the PI3K/Akt pathway plays a major role in regulating the cellular uptake of glucose, as well as the incorporation of this glucose carbon into lipids for membrane synthesis. Tyrosine-kinase-based regulation of key glycolytic enzymes such as pyruvate kinase also plays a critical role directing glucose carbon into anabolic pathways. In addition, the Myc transcription factor and mTOR kinase regulate the uptake and utilization of amino acids for protein and nucleic acid synthesis, as well as for the supply of intermediates to the mitochondrial Krebs cycle. However, the relationship between cellular signaling and metabolism is not unidirectional. Cells, by sensing levels of intracellular metabolites and the status of key metabolic pathways, can exert feedback control on signal transduction networks through multiple types of metabolite-derived protein modifications. These mechanisms allow cells to coordinate growth and division with their metabolic activity.
Receptor-mediated signal transduction, initiated by external growth factors, drives cell proliferation. It also reprograms cell metabolism to fulfill the biosynthetic needs of cell growth and division.
doi:10.1101/cshperspect.a006783
PMCID: PMC3385956  PMID: 22687276
14.  Calcium Signaling 
Calcium ions control diverse cellular processes (e.g., muscle contraction, exocytosis, and motility). Cells use a “toolkit” of channels, pumps, and cytosolic buffers to regulate calcium levels.
doi:10.1101/cshperspect.a011171
PMCID: PMC3385957  PMID: 22751152
15.  The Evolution of the Wnt Pathway 
Wnt genes are important regulators of embryogenesis and cell differentiation in vertebrates and insects. New data revealed by comparative genomics have now shown that members of the Wnt signaling pathway can be found in all clades of metazoans, but not in fungi, plants, or unicellular eukaryotes. This article focuses on new data from recent genomic analyses of several basal metazoan organisms, providing evidence that the Wnt pathway was a primordial signaling pathway during evolution. The formation of a Wnt signaling center at the site of gastrulation was instrumental for the formation of a primary, anterior–posterior body axis, which can be traced throughout animal evolution.
The Wnt pathway originated in pre-bilaterian metazoans. It served as a signaling center during gastrulation and was instrumental for the formation of a primary, anterior–posterior body axis.
doi:10.1101/cshperspect.a007922
PMCID: PMC3385961  PMID: 22751150
16.  Regulation and Function of Autophagy during Cell Survival and Cell Death 
Autophagy is an important catabolic process that delivers cytoplasmic material to the lysosome for degradation. Autophagy promotes cell survival by elimination of damaged organelles and proteins aggregates, as well as by facilitating bioenergetic homeostasis. Although autophagy has been considered a cell survival mechanism, recent studies have shown that autophagy can promote cell death. The core mechanisms that control autophagy are conserved between yeast and humans, but animals also possess genes that regulate autophagy that are not present in yeast. These regulatory differences may be explained by the need to control autophagy in a cell context-specific manner in multicellular animals, such as during cell survival and cell death. Autophagy was thought to be a bulk cytoplasmic degradation mechanism, but recent studies have shown that specific cargo is recruited for degradation. This suggests the possibility that either cell survival or death may be regulated by selective autophagic clearance of cytoplasmic material. Here we summarize the mechanisms that regulate autophagy and how they may contribute to cell survival and death.
Animal-specific autophagy-regulatory genes may control cell survival and death in a context-dependent manner. The selective autophagic clearance of cytoplasmic material may also be involved.
doi:10.1101/cshperspect.a008813
PMCID: PMC3367545  PMID: 22661635
17.  T-Cell Tolerance: Central and Peripheral 
Somatic recombination of TCR genes in immature thymocytes results in some cells with useful TCR specificities, but also many with useless or potentially self-reactive specificities. Thus thymic selection mechanisms operate to shape the T-cell repertoire. Thymocytes that have a TCR with low affinity for self-peptide–MHC complexes are positively selected to further differentiate and function in adaptive immunity, whereas useless ones die by neglect. Clonal deletion and clonal diversion (Treg differentiation) are the major processes in the thymus that eliminate or control self-reactive T cells. Although these processes are thought to be efficient, they fail to control self-reactivity in all circumstances. Thus, peripheral tolerance processes exist wherein self-reactive T cells become functionally unresponsive (anergy) or are deleted after encountering self-antigens outside of the thymus. Recent advances in mechanistic studies of central and peripheral T-cell tolerance are promoting the development of therapeutic strategies to treat autoimmune disease and cancer and improve transplantation outcome.
Clonal deletion and clonal diversion control self-reactive T cells in the thymus. Anergy and deletion of self-reactive T cells occur outside of the thymus.
doi:10.1101/cshperspect.a006957
PMCID: PMC3367546  PMID: 22661634
18.  On Oncogenes and Tumor Suppressor Genes in the Mammary Gland 
Well-known oncogenes (e.g., MYC) and tumor suppressor genes (e.g., TP53) are involved in breast cancer. But the roles of newly identified genes, microRNAs, and other noncoding RNAs in the disease have yet to be defined.
doi:10.1101/cshperspect.a013466
PMCID: PMC3367547  PMID: 22661637
19.  On Molecular Mechanisms Guiding Embryonic Mammary Gland Development 
In the adult, mammary gland development is strictly controlled by hormones. However, mammary gland development begins in the embryo and, during that time, is regulated by local signaling between the epithelium and adjacent tissues.
doi:10.1101/cshperspect.a013524
PMCID: PMC3367548  PMID: 22661638
20.  Signaling in Cell Differentiation and Morphogenesis 
All the information to make a complete, fully functional living organism is encoded within the genome of the fertilized oocyte. How is this genetic code translated into the vast array of cellular behaviors that unfold during the course of embryonic development, as the zygote slowly morphs into a new organism? Studies over the last 30 years or so have shown that many of these cellular processes are driven by secreted or membrane-bound signaling molecules. Elucidating how the genetic code is translated into instructions or signals during embryogenesis, how signals are generated at the correct time and place and at the appropriate level, and finally, how these instructions are interpreted and put into action, are some of the central questions of developmental biology. Our understanding of the causes of congenital malformations and disease has improved substantially with the rapid advances in our knowledge of signaling pathways and their regulation during development. In this article, I review some of the signaling pathways that play essential roles during embryonic development. These examples show some of the mechanisms used by cells to receive and interpret developmental signals. I also discuss how signaling pathways downstream from these signals are regulated and how they induce specific cellular responses that ultimately affect cell fate and morphogenesis.
As a zygote morphs into a new organism, certain signaling pathways (e.g., Hedgehog and Notch) play essential roles in controlling cellular behaviors. Deciphering crosstalk among the different pathways is a major challenge.
doi:10.1101/cshperspect.a008151
PMCID: PMC3367549  PMID: 22570373
21.  Deconstructing Pancreas Developmental Biology 
The relentless nature and increasing prevalence of human pancreatic diseases, in particular, diabetes mellitus and adenocarcinoma, has motivated further understanding of pancreas organogenesis. The pancreas is a multifunctional organ whose epithelial cells govern a diversity of physiologically vital endocrine and exocrine functions. The mechanisms governing the birth, differentiation, morphogenesis, growth, maturation, and maintenance of the endocrine and exocrine components in the pancreas have been discovered recently with increasing tempo. This includes recent studies unveiling mechanisms permitting unexpected flexibility in the developmental potential of immature and mature pancreatic cell subsets, including the ability to interconvert fates. In this article, we describe how classical cell biology, genetic analysis, lineage tracing, and embryological investigations are being complemented by powerful modern methods including epigenetic analysis, time-lapse imaging, and flow cytometry-based cell purification to dissect fundamental processes of pancreas development.
Pancreas organogenesis mechanisms are being unraveled with increasing tempo. Unexpectedly, some cells thought to be terminally differentiated may have flexible developmental potential.
doi:10.1101/cshperspect.a012401
PMCID: PMC3367550  PMID: 22587935
22.  RNA in Defense: CRISPRs Protect Prokaryotes against Mobile Genetic Elements 
The CRISPR/Cas system in prokaryotes provides resistance against invading viruses and plasmids. Three distinct stages in the mechanism can be recognized. Initially, fragments of invader DNA are integrated as new spacers into the repetitive CRISPR locus. Subsequently, the CRISPR is transcribed and the transcript is cleaved by a Cas protein within the repeats, generating short RNAs (crRNAs) that contain the spacer sequence. Finally, crRNAs guide the Cas protein machinery to a complementary invader target, either DNA or RNA, resulting in inhibition of virus or plasmid proliferation. In this article, we discuss our current understanding of this fascinating adaptive and heritable defense system, and describe functional similarities and differences with RNAi in eukaryotes.
Prokaryotes possess an adaptive defense mechanism that incorporates foreign DNA/RNA and generates short complementary RNAs that target sequences in invading viruses and plasmids for destruction.
doi:10.1101/cshperspect.a003657
PMCID: PMC3367551  PMID: 21441598
23.  Signaling Pathways in Cell Polarity 
A key function of signal transduction during cell polarization is the creation of spatially segregated regions of the cell cortex that possess different lipid and protein compositions and have distinct functions. Polarity can be initiated spontaneously or in response to signaling inputs from adjacent cells or soluble factors and is stabilized by positive-feedback loops. A conserved group of proteins, the Par proteins, plays a central role in polarity establishment and maintenance in many contexts. These proteins generate and maintain their distinct locations in cells by actively excluding one another from specific regions of the plasma membrane. The Par signaling pathway intersects with multiple other pathways that control cell growth, death, and organization.
Polarity segregates subcellular regions with distinct functions (e.g., axons vs. dendrites in a neuron). Par proteins are components of signaling pathways (e.g., kinases and adapter proteins) that establish and maintain polarity.
doi:10.1101/cshperspect.a009654
PMCID: PMC3367552  PMID: 22553378
24.  Hedgehog Signaling 
Hedgehog proteins are intercellular signaling molecules that play a central role in animal development. In response to the signal, Gli zinc finger proteins are shuttled along the primary cilium to the nucleus to activate target genes.
doi:10.1101/cshperspect.a011221
PMCID: PMC3367553  PMID: 22661636
25.  NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD) 
Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor–dependent LTP and LTD may constitute cellular substrates of learning and memory.
Calcium influx through synaptic NMDA receptors triggers long-term potentiation (LTP) and long-term depression (LTD). AMPA receptors are redistributed to either potentiate or weaken the synapse, and over time additional proteins are synthesized to maintain LTP or LTD.
doi:10.1101/cshperspect.a005710
PMCID: PMC3367554  PMID: 22510460

Results 1-25 (489)