Hot off the presses! Jun 26 Cell

The Jun 26 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• In This Issue
  - Cell 137(7):1161, 1163 (2009)
  
• Developmental Biology Select
  - Cell 137(7):1165, 1167 (2009)
  The role of chromatin regulation in development is the subject of this issue's Developmental Biology Select. Recent discoveries link glycosylation to the repression mediated by Polycomb group proteins and provide insight into a developmental disorder that stems from the loss of a histone methyltransferase. Other work sheds light on particular developmental transitions, including loss of plasticity during embryogenesis, the temporal control of Hox gene expression, and the impact of long-range chromatin interactions on T cell maturation.
• Seeing Green in Conference Season
  - Cell 137(7):1169-1171 (2009)
  Researchers and scientific organizations are becoming aware of the greenhouse-gas emissions and waste associated with attending scientific conferences. Fledgling efforts are now underway to address this problem by offering carbon offsets, recycling at conferences, reducing conference travel, or replacing meetings with teleconferences.
• Common Ancestry of the CENP-A Chaperones Scm3 and HJURP
  - Cell 137(7):1173-1174 (2009)
  
• Glycobiology: Moving into the Mainstream
  - Cell 137(7):1175-1176 (2009)
  
• GABA Keeps Up an Appetite for Life
  - Cell 137(7):1177-1179 (2009)
  In the arcuate nucleus of the hypothalamus, neurons that produce the neuropeptides NPY and AgRP play a vital role in the maintenance of energy homeostasis. In this issue, Wu et al. (2009) show that these neurons modulate feeding behavior in mice by providing GABAergic input to the parabrachial nucleus in the brainstem.
• Ironing Out a Midlife Crisis
  - Cell 137(7):1179-1181 (2009)
  There is a strong correlation between age, genomic instability, and the development of cancer. Working in yeast, Veatch et al. (2009) now propose that defects in the biogenesis of iron-sulfur clusters arising as a consequence of mitochondrial dysfunction contribute to the increase in genomic instability as cells age.
• The Juxtamembrane Region of EGFR Takes Center Stage
  - Cell 137(7):1181-1183 (2009)
  The activation process for the epidermal growth factor receptor (EGFR) involves formation of an asymmetric dimer of the tyrosine kinase domains. Jura et al. (2009) in this issue and Brewer et al. (2009) in Molecular Cell now demonstrate that the juxtamembrane region of EGFR plays a crucial role in stabilizing this dimer.
• Closing in on Mechanisms of Tissue Morphogenesis
  - Cell 137(7):1183-1185 (2009)
  It remains largely unknown how large-scale tissue movements during development emerge from the interplay of different tensile forces associated with actomyosin networks. Solon et al. (2009) now report that a ratchet-like mechanism drives the movement of epithelial sheets during dorsal closure in embryos of the fruit fly Drosophila.
• Fly Stem Cell Research Gets Infectious
  - Cell 137(7):1185-1187 (2009)
  To maintain tissue homeostasis, stem cells need to increase their proliferation rate to repair tissue damage caused by stress or infection. In this issue, Jiang et al. (2009) describe a regulatory feedback mechanism involving the Jak/Stat signaling pathway that enables stem cells of the fly midgut to accomplish this task.
• Plant Asymmetric Cell Division, Vive la Différence!
  - Cell 137(7):1189-1192 (2009)
  Although little is known about how asymmetric cell division in plants is regulated, recent discoveries provide a starting point for exploring the mechanisms underlying this process. These studies reveal parallels with asymmetric division in yeast and animals, but also point to regulated cell expansion as a new mechanism of asymmetric division in plants.
• CTCF: Master Weaver of the Genome
  - Cell 137(7):1194-1211 (2009)
  CTCF is a highly conserved zinc finger protein implicated in diverse regulatory functions, including transcriptional activation/repression, insulation, imprinting, and X chromosome inactivation. Here we re-evaluate data supporting these roles in the context of mechanistic insights provided by recent genome-wide studies and highlight evidence for CTCF-mediated intra- and interchromosomal contacts at several developmentally regulated genomic loci. These analyses support a primary role for CTCF in the global organization of chromatin architecture and suggest that CTCF may be a heritable component of an epigenetic system regulating the interplay between DNA methylation, higher-order chromatin structure, and lineage-specific gene expression.
• Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol
  - Cell 137(7):1213-1224 (2009)
  LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2. NPC2 binds cholesterol with its isooctyl side chain buried and its 3β-hydroxyl exposed. Here, we describe high-resolution structures of the N-terminal domain (NTD) of NPC1 and complexes with cholesterol and 25-hydroxycholesterol. NPC1(NTD) binds cholesterol in an orientation opposite to NPC2: 3β-hydroxyl buried and isooctyl side chain exposed. Cholesterol transfer from NPC2 to NPC1(NTD) requires reorientation of a helical subdomain in NPC1(NTD), enlarging the opening for cholesterol entry. NPC1 with point mutations in this subdomain (distinct from the binding subdomain) cannot accept cholesterol from NPC2 and cannot restore cholesterol exit from lysosomes in NPC1-deficient cells. We propose a working model wherein after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds! NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes.
• Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation
  - Cell 137(7):1225-1234 (2009)
  Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABAA receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABAA receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms t! hat eventually allow mice to eat.
• Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism
  - Cell 137(7):1235-1246 (2009)
  Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca2+ responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics ! of developmental brain disorders and serve as an invaluable tool for therapeutic development.
• Mitochondrial Dysfunction Leads to Nuclear Genome Instability via an Iron-Sulfur Cluster Defect
  - Cell 137(7):1247-1258 (2009)
  Mutations and deletions in the mitochondrial genome (mtDNA), as well as instability of the nuclear genome, are involved in multiple human diseases. Here, we report that in Saccharomyces cerevisiae, loss of mtDNA leads to nuclear genome instability, through a process of cell-cycle arrest and selection we define as a cellular crisis. This crisis is not mediated by the absence of respiration, but instead correlates with a reduction in the mitochondrial membrane potential. Analysis of cells undergoing this crisis identified a defect in iron-sulfur cluster (ISC) biogenesis, which requires normal mitochondrial function. We found that downregulation of nonmitochondrial ISC protein biogenesis was sufficient to cause increased genomic instability in cells with intact mitochondrial function. These results suggest mitochondrial dysfunction stimulates nuclear genome instability by inhibiting the production of ISC-containing protein(s), which are required for maintenance of nuclear! genome integrity. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.
• Genomic Antagonism between Retinoic Acid and Estrogen Signaling in Breast Cancer
  - Cell 137(7):1259-1271 (2009)
  Retinoic acid (RA) triggers antiproliferative effects in tumor cells, and therefore RA and its synthetic analogs have great potential as anticarcinogenic agents. Retinoic acid receptors (RARs) mediate RA effects by directly regulating gene expression. To define the genetic network regulated by RARs in breast cancer, we identified RAR genomic targets using chromatin immunoprecipitation and expression analysis. We found that RAR binding throughout the genome is highly coincident with estrogen receptor α (ERα) binding, resulting in a widespread crosstalk of RA and estrogen signaling to antagonistically regulate breast cancer-associated genes. ERα- and RAR-binding sites appear to be coevolved on a large scale throughout the human genome, often resulting in competitive binding activity at nearby or overlapping cis-regulatory elements. The highly coordinated intersection between these two critical nuclear hormone receptor signaling pathways provides a global mechanism for! balancing gene expression output via local regulatory interactions dispersed throughout the genome.
• A Synthetic Genetic Edge Detection Program
  - Cell 137(7):1272-1281 (2009)
  Edge detection is a signal processing algorithm common in artificial intelligence and image recognition programs. We have constructed a genetically encoded edge detection algorithm that programs an isogenic community of E. coli to sense an image of light, communicate to identify the light-dark edges, and visually present the result of the computation. The algorithm is implemented using multiple genetic circuits. An engineered light sensor enables cells to distinguish between light and dark regions. In the dark, cells produce a diffusible chemical signal that diffuses into light regions. Genetic logic gates are used so that only cells that sense light and the diffusible signal produce a positive output. A mathematical model constructed from first principles and parameterized with experimental measurements of the component circuits predicts the performance of the complete program. Quantitatively accurate models will facilitate the engineering of more complex biological b! ehaviors and inform bottom-up studies of natural genetic regulatory networks.
• X-Ray Structures of the Hexameric Building Block of the HIV Capsid
  - Cell 137(7):1282-1292 (2009)
  The mature capsids of HIV and other retroviruses organize and package the viral genome and its associated enzymes for delivery into host cells. The HIV capsid is a fullerene cone: a variably curved, closed shell composed of approximately 250 hexamers and exactly 12 pentamers of the viral CA protein. We devised methods for isolating soluble, assembly-competent CA hexamers and derived four crystallographically independent models that define the structure of this capsid assembly unit at atomic resolution. A ring of six CA N-terminal domains form an apparently rigid core, surrounded by an outer ring of C-terminal domains. Mobility of the outer ring appears to be an underlying mechanism for generating the variably curved lattice in authentic capsids. Hexamer-stabilizing interfaces are highly hydrated, and this property may be key to the formation of quasi-equivalent interactions within hexamers and pentamers. The structures also clarify the molecular basis for capsid assemb! ly inhibition and should facilitate structure-based drug design strategies.
• Mechanism for Activation of the EGF Receptor Catalytic Domain by the Juxtamembrane Segment
  - Cell 137(7):1293-1307 (2009)
  Signaling by the epidermal growth factor receptor requires an allosteric interaction between the kinase domains of two receptors, whereby one activates the other. We show that the intracellular juxtamembrane segment of the receptor, known to potentiate kinase activity, is able to dimerize the kinase domains. The C-terminal half of the juxtamembrane segment latches the activated kinase domain to the activator, and the N-terminal half of this segment further potentiates dimerization, most likely by forming an antiparallel helical dimer that engages the transmembrane helices of the activated receptor. Our data are consistent with a mechanism in which the extracellular domains block the intrinsic ability of the transmembrane and cytoplasmic domains to dimerize and activate, with ligand binding releasing this block. The formation of the activating juxtamembrane latch is prevented by the C-terminal tails in a structure of an inactive kinase domain dimer, suggesting how alter! native dimers can prevent ligand-independent activation.
• Exocytosis of Post-Golgi Vesicles Is Regulated by Components of the Endocytic Machinery
  - Cell 137(7):1308-1319 (2009)
  Post-Golgi vesicles target and deliver most biosynthetic cargoes to the cell surface. However, the molecules and mechanisms involved in fusion of these vesicles are not well understood. We have employed a system to simultaneously monitor release of luminal and membrane biosynthetic cargoes from individual post-Golgi vesicles. Exocytosis of these vesicles is not calcium triggered. Release of luminal cargo can be accompanied by complete, partial, or no release of membrane cargo. Partial and no release of membrane cargo of a fusing vesicle are fates associated with kiss-and-run exocytosis, and we find that these are the predominant mode of post-Golgi vesicle exocytosis. Partial cargo release by post-Golgi vesicles occurs because of premature closure of the fusion pore and is modulated by the activity of clathrin, actin, and dynamin. Our results demonstrate that these components of the endocytic machinery modulate the nature and extent of biosynthetic cargo delivery by pos! t-Golgi vesicles at the cell membrane.
• BASL Controls Asymmetric Cell Division in Arabidopsis
  - Cell 137(7):1320-1330 (2009)
  Development in multicellular organisms requires the organized generation of differences. A universal mechanism for creating such differences is asymmetric cell division. In plants, as in animals, asymmetric divisions are correlated with the production of cellular diversity and pattern; however, structural constraints imposed by plant cell walls and the absence of homologs of known animal or fungal cell polarity regulators necessitates that plants utilize new molecules and mechanisms to create asymmetries. Here, we identify BASL, a novel regulator of asymmetric divisions in Arabidopsis. In asymmetrically dividing stomatal-lineage cells, BASL accumulates in a polarized crescent at the cell periphery before division, and then localizes differentially to the nucleus and a peripheral crescent in self-renewing cells and their sisters after division. BASL presence at the cell periphery is critical for its function, and we propose that BASL represents a plant-specific solution! to the challenge of asymmetric cell division.
• Pulsed Forces Timed by a Ratchet-like Mechanism Drive Directed Tissue Movement during Dorsal Closure
  - Cell 137(7):1331-1342 (2009)
  Dorsal closure is a tissue-modeling process in the developing Drosophila embryo during which an epidermal opening is closed. It begins with the appearance of a supracellular actin cable that surrounds the opening and provides a contractile force. Amnioserosa cells that fill the opening produce an additional critical force pulling on the surrounding epidermal tissue. We show that this force is not gradual but pulsed and occurs long before dorsal closure starts. Quantitative analysis, combined with laser cutting experiments and simulations, reveals that tension-based dynamics and cell coupling control the force pulses. These constitutively pull the surrounding epidermal tissue dorsally, but the displacement is initially transient. It is translated into dorsal-ward movement only with the help of the actin cable, which acts like a ratchet, counteracting ventral-ward epidermis relaxation after force pulses. Our work uncovers a sophisticated mechanism of cooperative force ge! neration between two major forces driving morphogenesis.
• Cytokine/Jak/Stat Signaling Mediates Regeneration and Homeostasis in the Drosophila Midgut
  - Cell 137(7):1343-1355 (2009)
  Cells in intestinal epithelia turn over rapidly due to damage from digestion and toxins produced by the enteric microbiota. Gut homeostasis is maintained by intestinal stem cells (ISCs) that divide to replenish the intestinal epithelium, but little is known about how ISC division and differentiation are coordinated with epithelial cell loss. We show here that when enterocytes (ECs) in the Drosophila midgut are subjected to apoptosis, enteric infection, or JNK-mediated stress signaling, they produce cytokines (Upd, Upd2, and Upd3) that activate Jak/Stat signaling in ISCs, promoting their rapid division. Upd/Jak/Stat activity also promotes progenitor cell differentiation, in part by stimulating Delta/Notch signaling, and is required for differentiation in both normal and regenerating midguts. Hence, cytokine-mediated feedback enables stem cells to replace spent progeny as they are lost, thereby establishing gut homeostasis.
• Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors
  - Cell 137(7):1356 (2009)
  
• SnapShot: F Box Proteins II
  - Cell 137(7):1358.e1-1358.e2 (2009)