卵细胞与上皮细胞的极性相似与分异

卵细胞与上皮细胞的极性相似与分异 Cell Vol. 141, Issue 5, May 28, 2010 Featured Articles 特辑 Review 综述 Cell Polarity in Eggs and Epithelia: Parallels and Diversity p757 卵细胞与上皮细胞的极性:相似与分异 Featured Articles 特辑 Article 研究文章 Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice p775 Hoxb8变异小鼠病理性理毛行为的造血系统起源 Essay 评论 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 Articles 研究文章 1. Actin-Bundling Protein TRIOBP Forms Resilient Rootlets of Hair Cell Stereocilia Essential for Hearing p786 肌动蛋白集束蛋白TRIOBP形成对听觉感知至关重要的毛细胞静纤毛的弹性 细根 2(Viral Reorganization of the Secretory Pathway Generates Distinct Organelles for RNA Replication p799 分泌途径的病毒识别产生用于RNA复制的特殊细胞器 2+3. The Structure of an Arf-ArfGAP Complex Reveals a Ca Regulatory Mechanism p812 2+Arf-ArfGAP复合物的结构揭示一个Ca调节机制 4(Peptidoglycan Crosslinking Relaxation Promotes Helicobacter pylori's Helical Shape and Stomach Colonization p822 肽聚糖交联的松解促进幽门螺杆菌螺旋形态的形成以及在胃内的定植 5,A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain p834 一种二价的狼蛛毒素通过靶定外孔结构域激活辣椒素受体TRPV1 6,Two Cyclin-Dependent Kinase Pathways Are Essential for Polarized Trafficking of Presynaptic Components p846 两个周期蛋白依赖性的激酶通路在突触前组分的极向运输中至关重要 7. Caspase-3 Activation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization p859 半胱天冬酶-3通过线粒体的活化为长时程抑制以及AMPA受体的内化所必 须 8. Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations p872 生理氧浓度下X失活前人胚胎干细胞的诱导 Theory 理论 Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics p884 配体特异性的c-Fos表达从ErbB网络动力学的时空控制中浮出水面 Resource 资源 Precision Mapping of an In Vivo N-Glycoproteome Reveals Rigid Topological and Sequence Constraints p897 一个糖蛋白组的在体精确测绘揭示拓扑以及序列上的严格限制 Snapshot 快照 SnapShot: Neuroligin-Neurexin Complexes p908 SnapShot:神经粘附分子Neuroligin-Neurexin复合物 Featured Articles 特辑 Review 综述 Cell Polarity in Eggs and Epithelia: Parallels and Diversity p757 卵细胞与上皮细胞的极性:相似与分异 Daniel St Johnston, Julie Ahringer Summary: Cell polarity, the generation of cellular asymmetries, is necessary for diverse processes in animal cells, 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 between 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 特辑 Article 研究文章 Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice p775 Hoxb8变异小鼠病理性理毛行为的造血系统起源 Shau-Kwaun Chen, Petr Tvrdik, Erik Peden, Scott Cho, Sen Wu, Gerald Spangrude, Mario R. Capecchi Summary: Mouse Hoxb8 mutants show unexpected behavior manifested by compulsive grooming and hair 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 bone 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 experiments 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 disorders, but the causative relationships are unclear. In this mouse, a distinct compulsive behavioral disorder is associated with mutant microglia. Essay 评论 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. Krogan Summary: Traditionally, 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 quantitative 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 肌动蛋白集束蛋白TRIOBP形成对听觉感知至关重要的毛细胞静纤毛的弹 性细根 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, Gregory I. Frolenkov, Thomas B. Friedman Summary: 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 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 filaments into uniquely dense bundles reminiscent of rootlets but distinct from bundles formed by espin, an actin ex8/ex8crosslinker in stereocilia. We generated mutant Triobp mice (Triobp) that are ex8/ex8profoundly deaf. Stereocilia of Triobp mice develop normally but fail to form rootlets and are easier 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. 2(Viral Reorganization of the Secretory Pathway Generates Distinct Organelles for RNA Replication p799 分泌途径的病毒识别产生用于RNA复制的特殊细胞器 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- Bonnet Summary: Many RNA 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 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 IIIβ (PI4KIIIβ) 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; PI4KIIIβ inhibition interferes with this process; and enteroviral 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. 2+3. The Structure of an Arf-ArfGAP Complex Reveals a Ca Regulatory Mechanism p812 2+Arf-ArfGAP复合物的结构揭示一个Ca调节机制 Shehab A. Ismail, Ingrid R. Vetter, Begona Sot, Alfred Wittinghofer Summary: 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 mechanism 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 (Arf6)clarifies the ArfGAP catalytic mechanism and shows a glutamine and an arginine (ASAP3)finger as the important catalytic residues. Unexpectedly 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 any other calcium-regulated processes and hints at a crosstalk 2+between Ca and Arf signaling. 4(Peptidoglycan Crosslinking Relaxation Promotes Helicobacter pylori's Helical Shape and Stomach Colonization p822 肽聚糖交联的松解促进幽门螺杆菌螺旋形态的形成以及在胃内的定植 Laura K. Sycuro, Zachary Pincus, Kimberley D. Gutierrez, Jacob Biboy, Chelsea A. Stern, Waldemar Vollmer, Nina R. Salama Summary: 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 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. Intact 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 pathway 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. 5,A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain p834 一种二价的狼蛛毒素通过靶定外孔结构域激活辣椒素受体TRPV1 Christopher J. Bohlen, Avi Priel, Sharleen Zhou, David King, Jan Siemens, David Julius Summary: Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and 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 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 channels during activation. 6,Two Cyclin-Dependent Kinase Pathways Are Essential for Polarized Trafficking of Presynaptic Components p846 两个周期蛋白依赖性的激酶通路在突触前组分的极向运输中至关重要 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. Jorgensen, Nancy Y. Ip, Kang Shen Summary: 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 components 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 the 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 suppressed 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 Activation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization p859 半胱天冬酶-3通过线粒体的活化为长时程抑制以及AMPA受体的内化所必 须 Zheng Li, Jihoon Jo, Jie-Min Jia, Shih-Ching Lo, Daniel J. Whitcomb, Song Jiao, Kwangwook Cho, Morgan Sheng Summary: NMDA receptor-dependent synaptic modifications, such as 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 mitochondria 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 prevented 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 causal link between the molecular mechanisms of apoptosis and LTD. 8. Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations p872 生理氧浓度下X失活前人胚胎干细胞的诱导 Christopher J. Lengner, Alexander A. Gimelbrant, Jennifer A. Erwin, Albert Wu Cheng, Matthew G. Guenther, G. Grant 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 Mitalipova Summary: The presence of two active X chromosomes (XaXa) is a hallmark of the ground state of pluripotency 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 concentrations. 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 the 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 culture under physiological oxygen. Theory 理论 Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics p884 配体特异性的c-Fos表达从ErbB网络动力学的时空控制中浮出水面 Takashi Nakakuki, Marc R. Birtwistle, Yuko Saeki, Noriko Yumoto, Kaori Ide, Takeshi Nagashima, Lutz Brusch, Babatunde A. Ogunnaike, Mariko Okada- Hatakeyama, Boris N. Kholodenko Summary: 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 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 existence of a HRG-induced repressor of c-fos transcription. Further experiments confirmed that this repressor is mainly induced by HRG, but not EGF, and requires new protein synthesis. We show how a spatially distributed, signaling-transcription cascade robustly discriminates between transient and sustained ERK activities at the c-Fos system level. The proposed control mechanisms are general and operate in different cell types, stimulated by various ligands. Resource 资源 Precision Mapping of an In Vivo N-Glycoproteome Reveals Rigid Topological and Sequence Constraints p897 一个糖蛋白组的在体精确测绘揭示拓扑以及序列上的严格限制 Dorota F. Zielinska, Florian Gnad, Jacek R. Wi?niewski, Matthias Mann Summary: N-linked glycosylation is a biologically important protein modification, but only a small fraction of modification sites have been mapped. We developed a filter aided sample preparation (FASP)-based method in which glycopeptides are enriched by binding to lectins on the top of a filter and mapped 6367 N-glycosylation sites on 2352 proteins in four mouse tissues and blood plasma using high-accuracy mass spectrometry. We found 74% of known mouse N-glycosites and discovered an additional 5753 sites on a diverse range of proteins. Sites almost always have the N-!P-[S|T]-!P (where !P is not proline) and rarely the N-X-C motif or nonconsensus sequences. Combining the FASP approach with analysis of subcellular glycosite localization reveals that the sites always orient toward the extracellular space or toward the lumen of ER, Golgi, lysosome, or peroxisome. The N-glycoproteome contains a plethora of modification sites on factors important in development, organ-specific functions, and disease. Snapshot 快照 SnapShot: Neuroligin-Neurexin Complexes p908 SnapShot:神经粘附分子Neuroligin-Neurexin复合物 Stéphane Baudouin, Peter Scheiffele