1、Cell Vol. 141, Issue 5, May 28, 2010Featured Articles 特輯Review 綜述Cell Polarity in Eggs and Epithelia: Parallels and Diversity p757卵細胞與上皮細胞的極性：相似與分異Featured Articles 特輯Article 研究文章Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice p775Hoxb8變異小鼠病理性理毛行為的造血系統(tǒng)起源Essay 評論Quantitative Geneti

2、c Interactions Reveal Biological Modularity p739基因相互作用的定量分析揭示生物的模式性Articles 研究文章1. Actin-Bundling Protein TRIOBP Forms Resilient Rootlets of Hair Cell Stereocilia Essential for Hearing p786肌動蛋白集束蛋白TRIOBP形成對聽覺感知至關重要的毛細胞靜纖毛的彈性細根 2Viral Reorganization of the Secretory Pathway Generates Distinct Organel

3、les for RNA Replication p799分泌途徑的病毒識別產(chǎn)生用于RNA復制的特殊細胞器3. The Structure of an Arf-ArfGAP Complex Reveals a Ca2+ Regulatory Mechanism p812Arf-ArfGAP復合物的結構揭示一個Ca2+調(diào)節(jié)機制4Peptidoglycan Crosslinking Relaxation Promotes Helicobacter pylori's Helical Shape and Stomach Colonization p822 肽聚糖交聯(lián)的松解促進幽門螺桿菌螺旋形態(tài)的

4、形成以及在胃內(nèi)的定植5A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain p834一種二價的狼蛛毒素通過靶定外孔結構域激活辣椒素受體TRPV16Two Cyclin-Dependent Kinase Pathways Are Essential for Polarized Trafficking of Presynaptic Components p846兩個周期蛋白依賴性的激酶通路在突觸前組分的極向運輸中至關重要7. Caspase-3 A

5、ctivation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization p859半胱天冬酶-3通過線粒體的活化為長時程抑制以及AMPA受體的內(nèi)化所必須8. Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations p872生理氧濃度下X失活前人胚胎干細胞的誘導Theory 理論Ligand-Specific c-Fos Expr

6、ession Emerges from the Spatiotemporal Control of ErbB Network Dynamics p884配體特異性的c-Fos表達從ErbB網(wǎng)絡動力學的時空控制中浮出水面Resource 資源Precision Mapping of an In Vivo N-Glycoproteome Reveals Rigid Topological and Sequence Constraints p897一個糖蛋白組的在體精確測繪揭示拓撲以及序列上的嚴格限制Snapshot 快照SnapShot: Neuroligin-Neurexin Complexes

7、 p908 SnapShot：神經(jīng)粘附分子Neuroligin-Neurexin復合物Featured Articles 特輯Review 綜述Cell Polarity in Eggs and Epithelia: Parallels and Diversity p757卵細胞與上皮細胞的極性：相似與分異Daniel St Johnston, Julie AhringerSummary: Cell polarity, the generation of cellular asymmetries, is necessary for diverse processes in animal cel

8、ls, such as cell migration, asymmetric cell division, epithelial barrier function, and morphogenesis. Common mechanisms generate and transduce cell polarity in different cells, but cell type-specific processes are equally important. In this review, we highlight the similarities and differences betwe

9、en the polarity mechanisms in eggs and epithelia. We also highlight the prospects for future studies on how cortical polarity interfaces with other cellular processes, such as morphogenesis, exocytosis, and lipid signaling, and how defects in polarity contribute to tumor formation.Featured Articles

10、特輯Article 研究文章Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice p775Hoxb8變異小鼠病理性理毛行為的造血系統(tǒng)起源Shau-Kwaun Chen, Petr Tvrdik, Erik Peden, Scott Cho, Sen Wu, Gerald Spangrude, Mario R. CapecchiSummary: Mouse Hoxb8 mutants show unexpected behavior manifested by compulsive grooming and hair

11、 removal, similar to behavior in humans with the obsessive-compulsive disorder spectrum disorder trichotillomania. As Hox gene disruption often has pleiotropic effects, the root cause of this behavioral deficit was unclear. Here we report that, in the brain, Hoxb8 cell lineage exclusively labels bon

12、e marrow-derived microglia. Furthermore, transplantation of wild-type bone marrow into Hoxb8 mutant mice rescues their pathological phenotype. It has been suggested that the grooming dysfunction results from a nociceptive defect, also exhibited by Hoxb8 mutant mice. However, bone marrow transplant e

13、xperiments and cell type-specific disruption of Hoxb8 reveal that these two phenotypes are separable, with the grooming phenotype derived from the hematopoietic lineage and the sensory defect derived from the spinal cord cells. Immunological dysfunctions have been associated with neuropsychiatric di

14、sorders, but the causative relationships are unclear. In this mouse, a distinct compulsive behavioral disorder is associated with mutant microglia.Essay 評論Quantitative Genetic Interactions Reveal Biological Modularity p739基因相互作用的定量分析揭示生物的模式性Pedro Beltrao, Gerard Cagney, Nevan J. KroganSummary: Tradi

15、tionally, research has been reductionist, characterizing the individual components of biological systems. But new technologies have increased the size and scope of biological data, and systems approaches have broadened the view of how these components are interconnected. Here, we discuss how quantit

16、ative mapping of genetic interactions enhances our view of biological systems, allowing their deeper interrogation across different biological scales.Articles 研究文章1. Actin-Bundling Protein TRIOBP Forms Resilient Rootlets of Hair Cell Stereocilia Essential for Hearing p786肌動蛋白集束蛋白TRIOBP形成對聽覺感知至關重要的毛細

17、胞靜纖毛的彈性細根 Shin-ichiro Kitajiri, Takeshi Sakamoto, Inna A. Belyantseva, Richard J. Goodyear, Ruben Stepanyan, Ikuko Fujiwara, Jonathan E. Bird, Saima Riazuddin, Sheikh Riazuddin, Zubair M. Ahmed, Jenny E. Hinshaw, James Sellers, James R. Bartles, John A. Hammer, Guy P. Richardson, Andrew J. Griffith,

18、 Gregory I. Frolenkov, Thomas B. FriedmanSummary: Inner ear hair cells detect sound through deflection of mechanosensory stereocilia. Each stereocilium is supported by a paracrystalline array of parallel actin filaments that are packed more densely at the base, forming a rootlet extending into

19、the cell body. The function of rootlets and the molecules responsible for their formation are unknown. We found that TRIOBP, a cytoskeleton-associated protein mutated in human hereditary deafness DFNB28, is localized to rootlets. In vitro, purified TRIOBP isoform 4 protein organizes actin filam

20、ents into uniquely dense bundles reminiscent of rootlets but distinct from bundles formed by espin, an actin crosslinker in stereocilia. We generated mutant Triobp mice (Triobpex8/ex8) that are profoundly deaf. Stereocilia of Triobpex8/ex8 mice develop normally but fail to form rootlets and are easi

21、er to deflect and damage. Thus, F-actin bundling by TRIOBP provides durability and rigidity for normal mechanosensitivity of stereocilia and may contribute to resilient cytoskeletal structures elsewhere.2Viral Reorganization of the Secretory Pathway Generates Distinct Organelles for RNA Re

22、plication p799分泌途徑的病毒識別產(chǎn)生用于RNA復制的特殊細胞器Nai-Yun Hsu, Olha Ilnytska, Georgiy Belov, Marianita Santiana, Ying-Han Chen, Peter M. Takvorian, Cyrilla Pau, Hilde van der Schaar, Neerja Kaushik-Basu, Tamas Balla, Craig E. Cameron, Ellie Ehrenfeld, Frank J.M. van Kuppeveld, Nihal Altan-BonnetSummary: Many RN

23、A viruses remodel intracellular membranes to generate specialized sites for RNA replication. How membranes are remodeled and what properties make them conducive for replication are unknown. Here we show how RNA viruses can manipulate multiple components of the cellular secretory pathway to generate

24、organelles specialized for replication that are distinct in protein and lipid composition from the host cell. Specific viral proteins modulate effector recruitment by Arf1 GTPase and its guanine nucleotide exchange factor GBF1, promoting preferential recruitment of phosphatidylinositol-4-kinase

25、 III (PI4KIII) to membranes over coat proteins, yielding uncoated phosphatidylinositol-4-phosphate (PI4P) lipid-enriched organelles. The PI4P-rich lipid microenvironment is essential for both enteroviral and flaviviral RNA replication; PI4KIII inhibition interferes with this process; and enteroviral

26、 RNA polymerases specifically bind PI4P. These findings reveal how RNA viruses can selectively exploit specific elements of the host to form specialized organelles where cellular phosphoinositide lipids are key to regulating viral RNA replication.3. The Structure of an Arf-ArfGAP Complex Reveals a C

27、a2+ Regulatory Mechanism p812Arf-ArfGAP復合物的結構揭示一個Ca2+調(diào)節(jié)機制Shehab A. Ismail, Ingrid R. Vetter, Begona Sot, Alfred WittinghoferSummary: Arfs are small G proteins that have a key role in vesicle trafficking and cytoskeletal remodeling. ArfGAP proteins stimulate Arf intrinsic GTP hydrolysis by a mechanis

28、m that is still unresolved. Using a fusion construct we solved the structure of the ArfGAP ASAP3 in complex with Arf6 in the transition state. This structure clarifies the ArfGAP catalytic mechanism and shows a glutamine(Arf6) and an arginine finger(ASAP3) as the important catalytic residues. Unexpe

29、ctedly the structure shows a calcium ion, liganded by both proteins in the complex interface, stabilizing the interaction and orienting the catalytic machinery. Calcium stimulates the GAP activity of ASAPs, but not other members of the ArfGAP family. This type of regulation is unique for GAPs and an

30、y other calcium-regulated processes and hints at a crosstalk between Ca2+ and Arf signaling.4Peptidoglycan Crosslinking Relaxation Promotes Helicobacter pylori's Helical Shape and Stomach Colonization p822 肽聚糖交聯(lián)的松解促進幽門螺桿菌螺旋形態(tài)的形成以及在胃內(nèi)的定植Laura K. Sycuro, Zachary Pincus, Kimberley D. Gutierrez, Jac

31、ob Biboy, Chelsea A. Stern, Waldemar Vollmer, Nina R. SalamaSummary: The mechanisms by which bacterial cells generate helical cell shape and its functional role are poorly understood. Helical shape of the human pathogen Helicobacter pylori may facilitate penetration of the thick gastric mucus where

32、it replicates. We identified four genes required for helical shape: three LytM peptidoglycan endopeptidase homologs (csd13) and a ccmA homolog. Surrounding the cytoplasmic membrane of most bacteria, the peptidoglycan (murein) sacculus is a meshwork of glycan strands joined by peptide crosslinks. Int

33、act cells and isolated sacculi from mutants lacking any single csd gene or ccmA formed curved rods and showed increased peptidoglycan crosslinking. Quantitative morphological analyses of multiple-gene deletion mutants revealed each protein uniquely contributes to a shape-generating pathway. This pat

34、hway is required for robust colonization of the stomach in spite of normal directional motility. Our findings suggest that the coordinated action of multiple proteins relaxes peptidoglycan crosslinking, enabling helical cell curvature and twist.5A Bivalent Tarantula Toxin Activates the Capsaicin Rec

35、eptor, TRPV1, by Targeting the Outer Pore Domain p834一種二價的狼蛛毒素通過靶定外孔結構域激活辣椒素受體TRPV1Christopher J. Bohlen, Avi Priel, Sharleen Zhou, David King, Jan Siemens, David JuliusSummary: Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, an

36、d have thus served as invaluable tools for probing channel structure and function. Here, we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high-avidity interaction derives from a unique tandem

37、 repeat structure of the toxin that endows it with an antibody-like bivalency. The double-knot toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP

38、 channels during activation.6Two Cyclin-Dependent Kinase Pathways Are Essential for Polarized Trafficking of Presynaptic Components p846兩個周期蛋白依賴性的激酶通路在突觸前組分的極向運輸中至關重要Chan-Yen Ou, Vivian Y. Poon, Celine I. Maeder, Shigeki Watanabe, Emily K. Lehrman, Amy K.Y. Fu, Mikyoung Park, Wing-Yu Fu, Erik M. Jor

39、gensen, Nancy Y. Ip, Kang ShenSummary: Polarized trafficking of synaptic proteins to axons and dendrites is crucial to neuronal function. Through forward genetic analysis in C. elegans, we identified a cyclin (CYY-1) and a cyclin-dependent Pctaire kinase (PCT-1) necessary for targeting presynaptic c

40、omponents to the axon. Another cyclin-dependent kinase, CDK-5, and its activator p35, act in parallel to and partially redundantly with the CYY-1/PCT-1 pathway. Synaptic vesicles and active zone proteins mostly mislocalize to dendrites in animals defective for both PCT-1 and CDK-5 pathways. Unlike t

41、he kinesin-3 motor, unc-104/Kif1a mutant, cyy-1 cdk-5 double mutants have no reduction in anterogradely moving synaptic vesicle precursors (SVPs) as observed by dynamic imaging. Instead, the number of retrogradely moving SVPs is dramatically increased. Furthermore, this mislocalization defect is sup

42、pressed by disrupting the retrograde motor, the cytoplasmic dynein complex. Thus, PCT-1 and CDK-5 pathways direct polarized trafficking of presynaptic components by inhibiting dynein-mediated retrograde transport and setting the balance between anterograde and retrograde motors.7. Caspase-3 Activati

43、on via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization p859半胱天冬酶-3通過線粒體的活化為長時程抑制以及AMPA受體的內(nèi)化所必須Zheng Li, Jihoon Jo, Jie-Min Jia, Shih-Ching Lo, Daniel J. Whitcomb, Song Jiao, Kwangwook Cho, Morgan ShengSummary: NMDA receptor-dependent synaptic modifications, such a

44、s long-term potentiation (LTP) and long-term depression (LTD), are essential for brain development and function. LTD occurs mainly by the removal of AMPA receptors from the postsynaptic membrane, but the underlying molecular mechanisms remain unclear. Here, we show that activation of caspase-3 via m

45、itochondria is required for LTD and AMPA receptor internalization in hippocampal neurons. LTD and AMPA receptor internalization are blocked by peptide inhibitors of caspase-3 and -9. In hippocampal slices from caspase-3 knockout mice, LTD is abolished whereas LTP remains normal. LTD is also pre

46、vented by overexpression of the anti-apoptotic proteins XIAP or Bcl-xL, and by a mutant Akt1 protein that is resistant to caspase-3 proteolysis. NMDA receptor stimulation that induces LTD transiently activates caspase-3 in dendrites, without causing cell death. These data indicate an unexpected caus

47、al link between the molecular mechanisms of apoptosis and LTD.8. Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations p872生理氧濃度下X失活前人胚胎干細胞的誘導Christopher J. Lengner, Alexander A. Gimelbrant, Jennifer A. Erwin, Albert Wu Cheng, Matthew G. Guenther, G. G

48、rant Welstead, Raaji Alagappan, Garrett M. Frampton, Ping Xu, Julien Muffat, Sandro Santagata, Doug Powers, C. Brent Barrett, Richard A. Young, Jeannie T. Lee, Rudolf Jaenisch, Maisam MitalipovaSummary: The presence of two active X chromosomes (XaXa) is a hallmark of the ground state of pluripotency

49、 specific to murine embryonic stem cells (ESCs). Human ESCs (hESCs) invariably exhibit signs of X chromosome inactivation (XCI) and are considered developmentally more advanced than their murine counterparts. We describe the establishment of XaXa hESCs derived under physiological oxygen concentratio

50、ns. Using these cell lines, we demonstrate that (1) differentiation of hESCs induces random XCI in a manner similar to murine ESCs, (2) chronic exposure to atmospheric oxygen is sufficient to induce irreversible XCI with minor changes of the transcriptome, (3) the Xa exhibits heavy methylation of th

51、e XIST promoter region, and (4) XCI is associated with demethylation and transcriptional activation of XIST along with H3K27-me3 deposition across the Xi. These findings indicate that the human blastocyst contains pre-X-inactivation cells and that this state is preserved in vitro through cultur

52、e under physiological oxygen.Theory 理論Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics p884配體特異性的c-Fos表達從ErbB網(wǎng)絡動力學的時空控制中浮出水面Takashi Nakakuki, Marc R. Birtwistle, Yuko Saeki, Noriko Yumoto, Kaori Ide, Takeshi Nagashima, Lutz Brusch, Babatunde A. Ogunna

53、ike, Mariko Okada-Hatakeyama, Boris N. KholodenkoSummary: Activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) determines distinct cell-fate decisions, although signals propagate through shared pathways. Using mathematical modeling and experimental approaches, we unravel

54、how HRG and EGF generate distinct, all-or-none responses of the phosphorylated transcription factor c-Fos. In the cytosol, EGF induces transient and HRG induces sustained ERK activation. In the nucleus, however, ERK activity and c-fos mRNA expression are transient for both ligands. Knockdown of dual-specificity phosphatases extends HRG-stimulated nuclear ERK activation, but not c-fos mRNA expression, implying the