Hot off the presses! Jun 01 Nat Rev Genet

The Jun 01 issue of the Nat Rev Genet is now up on Pubget (About Nat Rev Genet): 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:

• 
  - Nat Rev Genet 11(6):365 (2011)
  
• T cells: T cell fate in the (im)balance | PDF (168 KB)
  - Nat Rev Genet 11(6):367 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Innate immunity: Linking lipids and inflammasomes | PDF (247 KB)
  - Nat Rev Genet 11(6):368 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Monocytes: Nudged out of the niche | PDF (212 KB)
  - Nat Rev Genet 11(6):368 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Signalling: PI3Kβ — linking signals for neutrophil activation | PDF (103 KB)
  - Nat Rev Genet 11(6):369 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Cytokines: GM-CSF in focus | PDF (152 KB)
  - Nat Rev Genet 11(6):370 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• T cell responses: CD4s work the doors | PDF (261 KB)
  - Nat Rev Genet 11(6):370 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Phagocytosis: A synapse for snaps | PDF (240 KB)
  - Nat Rev Genet 11(6):371 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Antiviral immunity: TRIM5 moonlights as a pattern recognition receptor | PDF (140 KB)
  - Nat Rev Genet 11(6):372 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Innate immunity: GBPs coordinate vesicular trafficking for host defence | PDF (311 KB)
  - Nat Rev Genet 11(6):372 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Transplantation | Co-stimulation | Vaccines | PDF (89 KB)
  - Nat Rev Genet 11(6):372 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Neuroimmunology | NKT cells | Vaccines | PDF (98 KB)
  - Nat Rev Genet 11(6):373 (2011)
  When a T cell encounters its cognate antigen on an antigen-presenting cell, there is a rapid polarization of intracellular and transmembrane proteins towards the site of intercellular contact to form an immune synapse. Subsequent T cell activation leads to T cell proliferation and differentiation towards one of several T cell fates, depending on signals from the environment.
• Diversity and dialogue in immunity to helminths
  - Nat Rev Genet 11(6):375 (2011)
  The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.
• Mitochondria in innate immune responses
  - Nat Rev Genet 11(6):389 (2011)
  The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.
• The outs and the ins of sphingosine-1-phosphate in immunity
  - Nat Rev Genet 11(6):403 (2011)
  The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.
• The insider's guide to leukocyte integrin signalling and function
  - Nat Rev Genet 11(6):416 (2011)
  The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.
• Fibrocytes: emerging effector cells in chronic inflammation
  - Nat Rev Genet 11(6):427 (2011)
  The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.

Hot off the presses! Feb 01 Nat Rev Mol Cell Biol

The Feb 01 issue of the Nat Rev Mol Cell Biol is now up on Pubget (About Nat Rev Mol Cell Biol): 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:

• 
  - Nat Rev Mol Cell Biol 12(2):71 (2011)
  
• Membrane trafficking: A GSK3 lockdown | PDF (322 KB)
  - Nat Rev Mol Cell Biol 12(2):72 (2011)
  A vital step in the WNT signalling pathway is inhibition of glycogen synthase kinase 3 (GSK3), but how this takes place had remained elusive. It turns out that activation of WNT signalling drives GSK3 into multivesicular bodies (MVBs), effectively locking it away from cytosolic substrates.
• Cytoskeleton: N-WASP 'muscles in' on actin nucleation | PDF (184 KB)
  - Nat Rev Mol Cell Biol 12(2):73 (2011)
  Muscle maturation and hypertrophy require the activation of protein synthesis and myofibrillogenesis. Takano et al.
• 'Tit-for-tat' in cell biology | PDF (142 KB)
  - Nat Rev Mol Cell Biol 12(2):73 (2011)
  Although my colleagues (and, hopefully, readers) value the importance of evolutionary theory in biology, many of us fail to incorporate it into our research. Therefore, I am going to tell you about a paper that influenced me long ago.
• Cell migration: MTORC2 brings up the rear | PDF (191 KB)
  - Nat Rev Mol Cell Biol 12(2):74 (2011)
  Target of rapamycin complex 2 (TORC2) is known to have a role in the chemotaxis of Dictyostelium discoideum, and its mammalian counterpart, mTORC2, regulates cytoskeletal reorganization in some cell lines. Parent and colleagues now find that mTORC2 also has a role in neutrophil chemotaxis through control of cell-rear retraction.
• Cell migration: Keeping together | PDF (207 KB)
  - Nat Rev Mol Cell Biol 12(2):74 (2011)
  Collective cell movement — needed for normal development but also associated with the invasion of cancer cells — requires organization and coordination. An actomyosin force around the edge of a migrating cell cluster facilitates coordinated movement, but contractility at cell–cell contacts inside the cluster must be reduced to maintain group cohesion.
• Cell signalling: Targeting kinases | PDF (129 KB)
  - Nat Rev Mol Cell Biol 12(2):75 (2011)
  The spatial regulation of signalling pathways is partly controlled by protein domains that mediate intermolecular interactions. Human MARK (MAP/microtubule affinity-regulating kinases) and PAR1 (partitioning-defective 1) Ser/Thr kinases harbour a kinase-associated 1 (KA1) domain, which has no assigned function.
• Cell signalling: Weighing up TGFβ signals | PDF (145 KB)
  - Nat Rev Mol Cell Biol 12(2):76 (2011)
  Signalling through the Hippo pathway allows sensing of local cell density and subsequent control of cell growth, proliferation and apoptosis. The transcriptional regulators TAZ and YAP are key components in this response, and Varelas et al.
• Development: A new move for PRMT5 | PDF (178 KB)
  - Nat Rev Mol Cell Biol 12(2):76 (2011)
  To establish and maintain pluripotency, cells must tightly regulate gene expression. Protein Arg N-methyltransferase 5 (PRMT5) is crucial for the development of primordial germ cells, and there have been suggestions that it might also be involved in embryonic stem (ES) cell pluripotency.
• Gene expression | Autophagy | Stem cells | PDF (127 KB)
  - Nat Rev Mol Cell Biol 12(2):76 (2011)
  Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs François, V.et al. Nature Struct. Mol. Biol. 18, 85–87 (2011)
• Autophagy: Myosin II moves in on autophagosomes | PDF (135 KB)
  - Nat Rev Mol Cell Biol 12(2):77 (2011)
  During starvation-induced autophagy, cytosol or organelles are engulfed by autophagosomes, the contents of which are degraded by lysosomes and released as nutrients. The kinase Autophagy-related 1 (ATG1) is important for autophagosome formation, but its exact role was unclear.
• Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration
  - Nat Rev Mol Cell Biol 12(2):79 (2011)
  The ultimate goal of regenerative medicine is to replace lost or damaged cells. This can potentially be accomplished using the processes of dedifferentiation, transdifferentiation or reprogramming. Recent advances have shown that the addition of a group of genes can not only restore pluripotency in a fully differentiated cell state (reprogramming) but can also induce the cell to proliferate (dedifferentiation) or even switch to another cell type (transdifferentiation). Current research aims to understand how these processes work and to eventually harness them for use in regenerative medicine.
• The MRE11 complex: starting from the ends
  - Nat Rev Mol Cell Biol 12(2):90 (2011)
  The maintenance of genome stability depends on the DNA damage response (DDR), which is a functional network comprising signal transduction, cell cycle regulation and DNA repair. The metabolism of DNA double-strand breaks governed by the DDR is important for preventing genomic alterations and sporadic cancers, and hereditary defects in this response cause debilitating human pathologies, including developmental defects and cancer. The MRE11 complex, composed of the meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin) proteins is central to the DDR, and recent insights into its structure and function have been gained from in vitro structural analysis and studies of animal models in which the DDR response is deficient.
• Feedback regulation of EGFR signalling: decision making by early and delayed loops
  - Nat Rev Mol Cell Biol 12(2):104 (2011)
  Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks — such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer.
• Origins of regulated cell-to-cell variability
  - Nat Rev Mol Cell Biol 12(2):119 (2011)
  Single-cell measurements and lineage-tracing experiments are revealing that phenotypic cell-to-cell variability is often the result of deterministic processes, despite the existence of intrinsic noise in molecular networks. In most cases, this determinism represents largely uncharacterized molecular regulatory mechanisms, which places the study of cell-to-cell variability in the realm of molecular cell biology. Further research in the field will be important to advance quantitative cell biology because it will provide new insights into the mechanisms by which cells coordinate their intracellular activities in the spatiotemporal context of the multicellular environment.
• The elusive nature and function of mesenchymal stem cells
  - Nat Rev Mol Cell Biol 12(2):126 (2011)
  Mesenchymal stem cells (MSCs) are a diverse subset of multipotent precursors present in the stromal fraction of many adult tissues and have drawn intense interest from translational and basic investigators. MSCs have been operationally defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes after in vitro expansion. Nevertheless, their identity in vivo, heterogeneity, anatomical localization and functional roles in adult tissue homeostasis have remained enigmatic and are only just starting to be uncovered.

Hot off the presses! Nov 01 Trends Cell Biol

The Nov 01 issue of the Trends Cell Biol is now up on Pubget (About Trends Cell Biol): 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:

• Editorial Board
  - Trends Cell Biol 21(11):i (2011)
  
• FORMIN a link between kinetochores and microtubule ends
  - Trends Cell Biol 21(11):625-629 (2011)
  The mammalian diaphanous-related (mDia) formin proteins are well known for their actin-nucleation and filament-elongation activities in mediating actin dynamics. They also directly bind to microtubules and regulate microtubule stabilization at the leading edge of the cell during cell migration. Recently, the formin mDia3 was shown to associate with the kinetochore and to contribute to metaphase chromosome alignment, a process in which kinetochores form stable attachments with growing and shrinking microtubules. We suggest that the formin mDia3 could contribute to the regulation of kinetochore-bound microtubule dynamics, in coordination with attachment via its own microtubule-binding activity, as well as via its interaction with the tip-tracker EB1 (end-binding protein 1).
• Ripped to death
  - Trends Cell Biol 21(11):630-637 (2011)
  An old puzzle in the field of cell death was solved recently: the mysterious embryonic lethality of animals deficient in caspase-8 or Fas-associated death domain (FADD), proteins involved in a pathway of apoptosis. This lethality is caused by a failure to develop the yolk sac vasculature rather than a lack of apoptosis. Remarkably, development is rescued by ablation of either of two receptor interacting serine-threonine kinases (RIPKs). Despite being well known cell killers, caspase-8 and FADD act together to block RIPK-mediated necrosis. To manifest this newly elucidated pro-survival function, FADD and caspase-8 depend on FLIPLong, a catalytically inactive caspase-8 homolog. In this review, the mechanism by which RIPK necrotic death is inhibited by this trio is discussed, as well as how RIPKs might themselves mediate cell death.
• Plithotaxis and emergent dynamics in collective cellular migration
  - Trends Cell Biol 21(11):638-646 (2011)
  For a monolayer sheet to migrate cohesively, it has long been suspected that each constituent cell must exert physical forces not only upon its extracellular matrix but also upon neighboring cells. The first comprehensive maps of these distinct force components reveal an unexpected physical picture. Rather than showing smooth and systematic variation within the monolayer, the distribution of physical forces is dominated by heterogeneity, both in space and in time, which emerges spontaneously, propagates over great distances, and cooperates over the span of many cell bodies. To explain the severe ruggedness of this force landscape and its role in collective cell guidance, the well known mechanisms of chemotaxis, durotaxis, haptotaxis are clearly insufficient. In a broad range of epithelial and endothelial cell sheets, collective cell migration is governed instead by a newly discovered emergent mechanism of innately collective cell guidance – plithotaxis.
• Endosomal transport via ubiquitination
  - Trends Cell Biol 21(11):647-655 (2011)
  Cell survival, growth, differentiation and homeostasis rely on exquisite control of the abundance of particular cell-surface membrane proteins. Cell-surface proteins must respond appropriately to environmental and intracellular cues, often undergoing regulated internalization and lysosomal degradation. These proteins also can sustain damage and must be recognized and removed. A unifying mechanism has emerged for the trafficking of damaged and downregulated proteins to the lysosome by their attachment to ubiquitin (Ub), which serves as a sorting signal for clathrin-mediated internalization and sorting into late endosomes. Major questions remain as to how this system is governed, how it is adapted for different proteins, and whether Ub serves as more than a one-way ticket to the lysosome for degradation. Here, we highlight recent insights and the challenges that remain.
• K11-linked ubiquitin chains as novel regulators of cell division
  - Trends Cell Biol 21(11):656-663 (2011)
  Modification of proteins with ubiquitin chains is an essential regulatory event in cell cycle control. Differences in the connectivity of ubiquitin chains are believed to result in distinct functional consequences for the modified proteins. Among eight possible homogenous chain types, canonical Lys48-linked ubiquitin chains have long been recognized to drive the proteasomal degradation of cell cycle regulators, and Lys48 is the only essential lysine residue of ubiquitin in yeast. It thus came as a surprise that in higher eukaryotes atypical K11-linked ubiquitin chains regulate the substrates of the anaphase-promoting complex and control progression through mitosis. We discuss recent findings that shed light on the assembly and function of K11-linked chains during cell division.
• Phytochrome signaling mechanisms and the control of plant development
  - Trends Cell Biol 21(11):664-671 (2011)
  As they emerge from the ground, seedlings adopt a photosynthetic lifestyle, which is accompanied by dramatic changes in morphology and global alterations in gene expression that optimizes the plant body plan for light capture. Phytochromes are red and far-red photoreceptors that play a major role during photomorphogenesis, a complex developmental program that seedlings initiate when they first encounter light. The earliest phytochrome signaling events after excitation by red light include their rapid translocation from the cytoplasm to subnuclear bodies (photobodies) that contain other proteins involved in photomorphogenesis, including a number of transcription factors and E3 ligases. In the light, phytochromes and negatively acting transcriptional regulators that interact directly with phytochromes are destabilized, whereas positively acting transcriptional regulators are stabilized. Here, we discuss recent advances in our knowledge of the mechanisms linking phytochro! me photoactivation in the cytoplasm and transcriptional regulation in the nucleus.
• Coordinating cell polarity with cell division in space and time
  - Trends Cell Biol 21(11):672-680 (2011)
  Decisions of when and where to divide are crucial for cell survival and fate, and for tissue organization and homeostasis. The temporal coordination of mitotic events during cell division is essential to ensure that each daughter cell receives one copy of the genome. The spatial coordination of these events is also crucial because the cytokinetic furrow must be aligned with the axis of chromosome segregation and, in asymmetrically dividing cells, the polarity axis. Several recent papers describe how cell shape and polarity are coordinated with cell division in single cells and tissues and begin to unravel the underlying molecular mechanisms, revealing common principles and molecular players. Here, we discuss how cells regulate the spatial and temporal coordination of cell polarity with cell division.

Hot off the presses! Oct 01 Trends Cell Biol

The Oct 01 issue of the Trends Cell Biol is now up on Pubget (About Trends Cell Biol): 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:

• Editorial Board
  - Trends Cell Biol 19(10):i (2009)
  
• The regulation of aging: does autophagy underlie longevity?
  - Trends Cell Biol 19(10):487-494 (2009)
  The accumulation of cellular damage is a feature common to all aging cells and leads to decreased ability of the organism to survive. The overall rate at which damage accumulates is influenced by conserved metabolic factors (longevity pathways and regulatory proteins) that control lifespan through adjusting mechanisms for maintenance and repair. Autophagy, the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles, is implicated in aging and in the incidence of diverse age-related pathologies. Recent evidence has revealed that autophagic activity is required for lifespan extension in various long-lived mutant organisms, and that numerous autophagy-related genes or proteins are directly regulated by longevity pathways. These findings support the emerging view that autophagy is a central regulatory mechanism for aging in diverse eukaryotic species.
• Plasmodesmata – bridging the gap between neighboring plant cells
  - Trends Cell Biol 19(10):495-503 (2009)
  Land plants have developed highly sophisticated intercellular channels called plasmodesmata (PD) that mediate the cell-to-cell trafficking of signaling molecules, including non-cell autonomous proteins (NCAPs) and RNAs. Until recently, the biological significance of this position-dependent intercellular signaling system was underestimated, as only a limited number of endogenous NCAPs had been discovered. However, identification of an ever-increasing population of NCAPs suggests that the PD communication pathway is involved in diverse biological processes, ranging from development to pathogen defense. The identification of components involved in plasmodesmal structure and associated signaling molecules is now yielding novel insights into the evolution and function of PD in mediating the trafficking of non-cell-autonomous information macromolecules. Important future challenges are to build a detailed model for the plasmodesmal supramolecular complex and to further elucid! ate the molecular and cellular aspects of this novel plant cell-to-cell communication pathway.
• The Kindlin protein family: new members to the club of focal adhesion proteins
  - Trends Cell Biol 19(10):504-513 (2009)
  Kindlins are a group of proteins that have recently attracted attention for their ability to bind and activate integrins. Moreover, they have also been linked to inherited and acquired human diseases including Kindler syndrome, leukocyte adhesion deficiency, and cancer. Although most studies have focused on kindlins as key regulatory components of cell–extracellular matrix junctions such as focal adhesions, preliminary data suggest the involvement of additional cellular compartments in mediating their functions, particularly at cell–cell contacts and the nucleus. Investigating the many roles of kindlins is likely to expand and sharpen our view on the versatility of integrin-mediated cell adhesion, the nuclear function of focal adhesion proteins, and the crosstalk between cell–cell and cell–matrix adhesions in health and disease.
• Molecular mediators of macrophage fusion
  - Trends Cell Biol 19(10):514-522 (2009)
  Fusion of macrophages leads to the formation of osteoclasts in bone and of multinucleated giant cells in granulomas. The precise function of granuloma-associated multinucleates giant cells is not clear but substantial progress has recently been made in identifying the molecular machinery involved in macrophage fusion. Signaling processes mediated by DAP12 and STAT6 induce a fusion-competent status. Chemotaxis through CCL2, cell–cell adhesion mediated by E-cadherin, exposure of phosphatidylserine, lipid recognition by CD36 and cytoskeletal rearrangements depending on RAC1 are prerequisites for successful macrophage fusion. We review current knowledge on the molecular mediators of giant cell formation, compare giant cells with osteoclasts and highlight key target areas for future research and medical relevance.
• Chemotaxis: finding the way forward with Dictyostelium
  - Trends Cell Biol 19(10):523-530 (2009)
  Understanding cell migration is centrally important to modern cell biology. However, despite years of study, progress has been hindered by experimental limitations and the complexity of the process. This has led to the popularity of Dictyostelium discoideum, with its experimentally-friendly lifestyle and small, haploid genome, as a tool to dissect the pathways involved in migration. This humble amoeba is now established at the centre of dramatic changes in our understanding of cell movement. In this review we describe the recent reinterpretation of the role of phosphatidylinositol trisphosphate (PIP3) and other intracellular messengers that connect signalling and migration, and the transition to models of chemotaxis driven by multiple, intertwined signalling pathways. In shallow gradients, pseudopods are generated with random directions, and we discuss how chemotaxis can operate by biasing this process. Overall we describe how Dictyostelium has the potential to unlock ! many fundamental questions in the cell motility field.
• Mitotic phosphatases: from entry guards to exit guides
  - Trends Cell Biol 19(10):531-541 (2009)
  While the importance of protein kinases for the spatial and temporal control of mitotic events has long been recognized, mitotic phosphatases have only recently come into the limelight. It is now well established that protein phosphatases counteract mitotic kinases, so contributing to the generation of switch-like responses at mitotic stage transitions. In addition, the timely dephosphorylation of mitotic phosphoproteins by tightly regulated phosphatases is required for the assembly and stability of the mitotic spindle, the initiation of anaphase, and exit from mitosis. Mitotic phosphatases also emerge as effectors of the DNA damage and spindle assembly checkpoints. These new findings show that protein phosphatases regulate every step of mitosis and provide novel insights into the dynamic and versatile nature of mitotic phosphoregulation.
• Crosstalk in Met receptor oncogenesis
  - Trends Cell Biol 19(10):542-551 (2009)
  The Met receptor tyrosine kinase (RTK) regulates several distinct biological processes, including cell scatter, cell invasion, cell survival and epithelial remodeling. MET is genetically altered through several mechanisms in multiple human cancers; these events are causally related to cancer initiation and progression, identifying Met as a potential therapeutic target. Recent evidence highlights additional roles for Met in cancer through crosstalk with other receptors and cell surface proteins. In this review, we discuss recent progress in our understanding of mechanisms of interaction between Met, the epidermal growth factor receptor family and other cell surface protein families, and how these contribute to signal crosstalk, oncogenesis and drug resistance.

Hot off the presses! Feb 01 Nat Rev Mol Cell Biol

The Feb 01 issue of the Nat Rev Mol Cell Biol is now up on Pubget (About Nat Rev Mol Cell Biol): 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:

• Stem cells: Self-help in the niche | PDF (144 KB)
  - Nat Rev Mol Cell Biol 13(2):61 (2012)
  Stem cells and progenitor cells reside in a microenvironment, or niche, that regulates their activity. Mondal et al.Drosophila melanogaster, differentiating blood cells themselves produce signals that, together with cues from the surrounding niche, contribute to the maintenance of their haematopoietic progenitors.
• Post-translational modification: Inactivating PTP1B upon ER stress | PDF (161 KB)
  - Nat Rev Mol Cell Biol 13(2):62 (2012)
  The gaseous signalling molecule hydrogen sulphide (H2S) regulates a range of cellular processes by causing the sulphydration of Cys residues (that is, the formation of Cys–SSH groups) in target proteins. Protein Tyr phosphatases (PTPs) use an essential Cys (Cys215) in their catalytic site to dephosphorylate Tyr residues in target proteins.
• Stem cells: Making fat | PDF (247 KB)
  - Nat Rev Mol Cell Biol 13(2):62 (2012)
  Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have the potential to produce patient-specific in vitro cell models to study disease. However, converting these cells into relevant adult cell types remains a challenge.
• Monkeys show the way | PDF (82 KB)
  - Nat Rev Mol Cell Biol 13(2):62 (2012)
  The first chimeric non-human primates have been generated in a laboratory in Oregon, USA. The work, which was reported in Cell, gave rise to three rhesus monkeys: Chimero and the twins Roku and Hex. The generation of chimeric mice has been an important tool for understanding normal embryonic development and disease and has indicated that embryonic stem (ES) cells are pluripotent and can give rise to all cell types. By carrying out research in monkeys, the group of Shoukhrat Mitalipov, at the Oregon National Primate Research Center, aimed to determine whether this also applies to primates, including humans, and whether human stem cells will have "potential, especially for regenerative medicine, where they can develop into mature and functional tissues and organs." (Reuters, 5 Jan 2012.) Interestingly, they observed that injection of cultured primate ES cells into blastocysts did not lead to the generation of chimaeras, unlike what is seen with mouse ES cells. Instead, chimaeras could be generated by aggregating cells from multiple four-cell embryos without prior culture. As commented by Mitalipov, "the cells never fuse, but they stay together and work together to form tissues and organs." (Scientific American, 6 Jan 2012.) The work has important implications; as commented by Robin Lovell-Badge, from the National Institute for Medical Research in Mill Hill, UK, "assumptions about the way human embryos develop have always been based on the mouse." (bbc.co.uk, 5 Jan 2012.) A related commentary in Cell postulates that this discrepancy could be due to differences in developmental status — primate ES cells may be more developmentally advanced than mouse ones. So, it seems that further work is needed in primates to better understand the properties of human ES cells.
• Ubiquitylation: DUBs' key to selectivity | PDF (124 KB)
  - Nat Rev Mol Cell Biol 13(2):64 (2012)
  Some deubiquitylating enzymes (DUBs) are specific for distinct ubiquitin linkages, but the molecular basis for this is largely unknown. TRABID, a DUB belonging to the ovarian tumour (OTU) family, has previously been shown to hydrolyze atypical Lys29-linked ubiquitin chains more efficiently than other linkages.
• Cell cycle: AMPK moonlights in mitosis | PDF (224 KB)
  - Nat Rev Mol Cell Biol 13(2):64 (2012)
  AMP-activated protein kinase (AMPK) is well known for its ability to regulate cell metabolism, but emerging evidence suggests that it functions in additional cellular processes. Banko et al.
• RNA decay: Remember your driver | PDF (140 KB)
  - Nat Rev Mol Cell Biol 13(2):65 (2012)
  The stability of mRNA is often assumed to be dictated by a transcript's sequence features. Two new studies highlight that mRNA stability can be influenced by a memory of the promoter from which expression of the transcript was driven.
• Post-translational modification: A monoubiquitylation pore anchor | PDF (181 KB)
  - Nat Rev Mol Cell Biol 13(2):66 (2012)
  The nuclear pore complex (NPC), which consists of ~30 nucleoporins (NUPs), has additional roles beyond its core function in nuclear transport. Post-translational modification of NUPs by ubiquitylation and phosphorylation can affect NUP turnover and pore disassembly, respectively, and may offer the opportunity for fine-tuning NUP functions beyond transport.
• How a paper on RAC set the standard | PDF (110 KB)
  - Nat Rev Mol Cell Biol 13(2):66 (2012)
  Modern cell biology is full of well-analysed signalling pathways that control every facet of a cell's life. To a student or postdoctoral researcher, it probably seems as if it has always been so, but it is a recent phenomenon.
• Cytoskeleton: Making multiple cilia | PDF (85 KB)
  - Nat Rev Mol Cell Biol 13(2):63 (2012)
  How centriole assembly and outgrowth of motile cilia are driven during multiciliate cell (MCC) differentiation is unclear, although Notch signalling is known to inhibit MCC formation in epithelia. Stubbs et al.Xenopus laevis skin, so they assessed its ability to promote MCC differentiation.
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  - Nat Rev Mol Cell Biol 13(2):63 (2012)
  
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  - Nat Rev Mol Cell Biol 13(2):63 (2012)
  
• Illuminating the functional and structural repertoire of human TBC/RABGAPs
  - Nat Rev Mol Cell Biol 13(2):67 (2012)
  The Tre2–Bub2–Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs) are characterized by the presence of highly conserved TBC domains and act as negative regulators of RABs. The importance of TBC/RABGAPs in the regulation of specific intracellular trafficking routes is now emerging, as is their role in different diseases. Importantly, TBC/RABGAPs act as key regulatory nodes, integrating signalling between RABs and other small GTPases and ensuring the appropriate retrieval, transport and delivery of different intracellular vesicles.
• Dynamin, a membrane-remodelling GTPase
  - Nat Rev Mol Cell Biol 13(2):75 (2012)
  Dynamin, the founding member of a family of dynamin-like proteins (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live-cell imaging, cell-free studies, X-ray crystallography and genetic studies in mice, has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged, highlighting specific contributions of this GTPase to the physiology of different tissues.
• The unfolded protein response: controlling cell fate decisions under ER stress and beyond
  - Nat Rev Mol Cell Biol 13(2):89 (2012)
  Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein-folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed.
• A family business: stem cell progeny join the niche to regulate homeostasis
  - Nat Rev Mol Cell Biol 13(2):103 (2012)
  Stem cell niches, the discrete microenvironments in which the stem cells reside, play a dominant part in regulating stem cell activity and behaviours. Recent studies suggest that committed stem cell progeny become indispensable components of the niche in a wide range of stem cell systems. These unexpected niche inhabitants provide versatile feedback signals to their stem cell parents. Together with other heterologous cell types that constitute the niche, they contribute to the dynamics of the microenvironment. As progeny are often located in close proximity to stem cell niches, similar feedback regulations may be the underlying principles shared by different stem cell systems.
• Understanding the language of Lys36 methylation at histone H3
  - Nat Rev Mol Cell Biol 13(2):115 (2012)
  Histone side chains are post-translationally modified at multiple sites, including at Lys36 on histone H3 (H3K36). Several enzymes from yeast and humans, including the methyltransferases SET domain-containing 2 (Set2) and nuclear receptor SET domain-containing 1 (NSD1), respectively, alter the methylation status of H3K36, and significant progress has been made in understanding how they affect chromatin structure and function. Although H3K36 methylation is most commonly associated with the transcription of active euchromatin, it has also been implicated in diverse processes, including alternative splicing, dosage compensation and transcriptional repression, as well as DNA repair and recombination. Disrupted placement of methylated H3K36 within the chromatin landscape can lead to a range of human diseases, underscoring the importance of this modification.
• Satellite cells, the engines of muscle repair
  - Nat Rev Mol Cell Biol 13(2):127 (2012)
  Satellite cells are a heterogeneous population of stem and progenitor cells that are required for the growth, maintenance and regeneration of skeletal muscle. The transcription factors paired-box 3 (PAX3) and PAX7 have essential and overlapping roles in myogenesis. PAX3 acts to specify embryonic muscle precursors, whereas PAX7 enforces the satellite cell myogenic programme while maintaining the undifferentiated state. Recent experiments have suggested that PAX7 is dispensable in adult satellite cells. However, these findings are controversial, and the issue remains unresolved.

Hot off the presses! Nov 16 dev cell

The Nov 16 issue of the dev cell is now up on Pubget (About dev 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:

• Myosin-II Puts the Squeeze on Asymmetric Cell Division
  - dev cell 19(5):639-640 (2010)
  Asymmetric cell division—where two dissimilar daughter cells are produced—relies on asymmetric positioning of the telophase spindle midzone, which specifies the cleavage furrow. Ou et al. (2010) now report in Science a mechanism of asymmetric midzone positioning driven by a polarized cortical distribution of the contractile motor myosin-II.
• Targeting p21 Degradation Locally
  - dev cell 19(5):641-643 (2010)
  Just as the activity of many multifunctional proteins is restricted by subcellular localization, so is their regulation. In this issue of Development Cell, Starostina et al. identify an E3 ubiquitin ligase, CRL2LRR1, for the cyclin-dependent kinase inhibitor p21 that specifically ubiquitylates cytoplasmic p21 to facilitate cell migration.
• Anthrax Toxins—Roadblocks for Exocytic Trafficking
  - dev cell 19(5):643-644 (2010)
  Anthrax toxins cause vascular dysfunction, in part by perturbing the endothelial cell barrier. Reporting in Nature, Guichard et al. shed new light on the mechanism by which this occurs and show that anthrax toxins interfere with exocytic delivery of cadherins to endothelial cell junctions by antagonizing the exocyst complex.
• Feeling UPBEAT about Growth: Linking ROS Gradients and Cell Proliferation
  - dev cell 19(5):644-646 (2010)
  Recent work in animals and plants suggests that reactive oxygen species (ROS) control cell proliferation. Reporting in Cell, Tsukagoshi et al. (2010) identify UPBEAT1 as a key transcription factor in the regulation of ROS distribution, which they find controls the transition between cell proliferation and differentiation in the Arabidopsis root.
• Global Approaches to Identify Novel Participants that Modulate Intestinal Epithelial Cell Development
  - dev cell 19(5):647-648 (2010)
  Combinatorial control of lineage-specific gene expression is commonly mediated by suites of diverse transcriptional regulators. In this issue of Developmental Cell, Verzi et al. (2010) use an unbiased global and computational approach to identify distinct partners and functions of CDX2 in intestinal epithelial cell differentiation.
• Tuning In to Noise: Epigenetics and Intangible Variation
  - dev cell 19(5):649-650 (2010)
  In this special issue of Developmental Cell, we discuss the role of chromatin in phenotypic variation as a counterpoint to the reviews on chromatin dynamics in development and cancer. We highlight some recent work on the role of chromatin in transcriptional noise in yeast and Caenorhabditis elegans and consider the implications in understanding intangible variation or developmental noise in mammals.
• Interpretation of Developmental Signaling at Chromatin: The Polycomb Perspective
  - dev cell 19(5):651-661 (2010)
  The Polycomb group (PcG) system represses the transcription of important developmental regulators and perpetuates this repression across multiple cell divisions. Inputs from outside the cell can influence PcG function by recruiting additional chromatin factors to PcG-regulated loci or by downregulating the PcG genes themselves. These types of PcG system modulation allow context-dependent induction of genes during development, in cancer, and in response to changes in the environment. In this review, we outline instances where molecular players in this process have been recently identified, comparing and contrasting different ways in which derepression is achieved, and projecting directions for future research.
• Histone Variants in Metazoan Development
  - dev cell 19(5):662-674 (2010)
  Embryonic development is regulated by both genetic and epigenetic mechanisms, with nearly all DNA-templated processes influenced by chromatin architecture. Sequence variations in histone proteins, core components of chromatin, provide a means to generate diversity in the chromatin structure, resulting in distinct and profound biological outcomes in the developing embryo. Emerging literature suggests that epigenetic contributions from histone variants play key roles in a number of developmental processes such as the initiation and maintenance of pericentric heterochromatin, X-inactivation, and germ cell differentiation. Here, we review the role of histone variants in the embryo with particular emphasis on early mammalian development.
• Epigenetic Transitions in Germ Cell Development and Meiosis
  - dev cell 19(5):675-686 (2010)
  Germ cell development is controlled by unique gene expression programs and involves epigenetic reprogramming of histone modifications and DNA methylation. The central event is meiosis, during which homologous chromosomes pair and recombine, processes that involve histone alterations. At unpaired regions, chromatin is repressed by meiotic silencing. After meiosis, male germ cells undergo chromatin remodeling, including histone-to-protamine replacement. Male and female germ cells are also differentially marked by parental imprints, which contribute to sex determination in insects and mediate genomic imprinting in mammals. Here, we review epigenetic transitions during gametogenesis and discuss novel insights from animal and human studies.
• Small RNA-Mediated Quiescence of Transposable Elements in Animals
  - dev cell 19(5):687-697 (2010)
  Transposable elements (TEs) are major components of the intergenic regions of the genome. However, TE transposition has the potential to threaten the reproductive fitness of the organism; therefore, organisms have evolved specialized molecular systems to sense and repress the expression of TEs to stop them from jumping to other genomic loci. Emerging evidence suggests that Argonaute proteins play a critical role in this process, in collaboration with two types of cellular small RNAs: PIWI-interacting RNAs (piRNAs) of the germline and endogenous small interfering RNAs (endo-siRNAs) of the soma, both of which are transcribed from TEs themselves.
• Aberrant Epigenetic Landscape in Cancer: How Cellular Identity Goes Awry
  - dev cell 19(5):698-711 (2010)
  Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of "resetting" the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed.
• Differentiation-Specific Histone Modifications Reveal Dynamic Chromatin Interactions and Partners for the Intestinal Transcription Factor CDX2
  - dev cell 19(5):713-726 (2010)
  Cell differentiation requires remodeling of tissue-specific gene loci and activities of key transcriptional regulators, which are recognized for their dominant control over cellular programs. Using epigenomic methods, we characterized enhancer elements specifically modified in differentiating intestinal epithelial cells and found enrichment of transcription factor-binding motifs corresponding to CDX2, a critical regulator of the intestine. Directed investigation revealed surprising lability in CDX2 occupancy of the genome, with redistribution from hundreds of sites occupied only in proliferating cells to thousands of new sites in differentiated cells. Knockout mice confirmed distinct Cdx2 requirements in dividing and mature adult intestinal cells, including responsibility for the active enhancer configuration associated with maturity. Dynamic CDX2 occupancy corresponds with condition-specific gene expression and, importantly, to differential co-occupancy with other tis! sue-restricted transcription factors, such as GATA6 and HNF4A. These results reveal dynamic, context-specific functions and mechanisms of a prominent transcriptional regulator within a cell lineage. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (20899 K)
• The NF2 Tumor Suppressor, Merlin, Regulates Epidermal Development through the Establishment of a Junctional Polarity Complex
  - dev cell 19(5):727-739 (2010)
  The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, is a FERM (Four point one, Ezrin, Radixin, Moesin) domain-containing protein whose loss results in defective morphogenesis and tumorigenesis in multiple tissues. Like the closely related ERM proteins (Ezrin, Radixin, and Moesin), Merlin may organize the plasma membrane by assembling membrane protein complexes and linking them to the cortical actin cytoskeleton. We previously found that Merlin is a critical mediator of contact-dependent inhibition of proliferation and is required for the establishment of stable adherens junctions (AJs) in cultured cells. Here, we delineate the molecular function of Merlin in AJ establishment in epidermal keratinocytes in vitro and confirm that a role in AJ establishment is an essential function of Merlin in vivo. Our studies reveal that Merlin can associate directly with α-catenin and link it to Par3, thereby providing an essential link between the AJ and the Par3 polarity co! mplex during junctional maturation.
• The Fz-Dsh Planar Cell Polarity Pathway Induces Oriented Cell Division via Mud/NuMA in Drosophila and Zebrafish
  - dev cell 19(5):740-752 (2010)
  The Frizzled receptor and Dishevelled effector regulate mitotic spindle orientation in both vertebrates and invertebrates, but how Dishevelled orients the mitotic spindle is unknown. Using the Drosophila S2 cell "induced polarity" system, we find that Dishevelled cortical polarity is sufficient to orient the spindle and that Dishevelled's DEP domain mediates this function. This domain binds a C-terminal domain of Mud (the Drosophila NuMA ortholog), and Mud is required for Dishevelled-mediated spindle orientation. In Drosophila, Frizzled-Dishevelled planar cell polarity (PCP) orients the sensory organ precursor (pI) spindle along the anterior-posterior axis. We show that Dishevelled and Mud colocalize at the posterior cortex of pI, Mud localization at the posterior cortex requires Dsh, and Mud loss-of-function randomizes spindle orientation. During zebrafish gastrulation, the Wnt11-Frizzled-Dishevelled PCP pathway orients spindles along the animal-vegetal axis, and ! reducing NuMA levels disrupts spindle orientation. Overall, we describe a Frizzled-Dishevelled-NuMA pathway that orients division from Drosophila to vertebrates.
• CRL2LRR-1 Targets a CDK Inhibitor for Cell Cycle Control in C. elegans and Actin-Based Motility Regulation in Human Cells
  - dev cell 19(5):753-764 (2010)
  The Cip/Kip CDK inhibitor (CKI) p21Cip1/WAF1 has a critical role in the nucleus to limit cell proliferation by inhibiting CDK-cyclin complexes. In contrast, cytoplasmic p21 regulates cell survival and the actin cytoskeleton. These divergent functions for p21 in different cellular compartments suggest the necessity for complex regulation. In this study, we identify the CRL2LRR-1 ubiquitin ligase as a conserved regulator of Cip/Kip CKIs that promotes the degradation of C. elegans CKI-1 and human p21. The nematode CRL2LRR-1 complex negatively regulates nuclear CKI-1 levels to ensure G1-phase cell cycle progression in germ cells. In contrast, human CRL2LRR1 targets cytoplasmic p21, acting as a critical regulator of cell motility that promotes a nonmotile stationary cell state by preventing p21 from inhibiting the Rho/ROCK/LIMK pathway. Inactivation of human CRL2LRR1 leads to the activation of the actin-depolymerizing protein cofilin, dramatic reorganization of the actin cy! toskeleton, and increased cell motility.
• Integration of Brassinosteroid Signal Transduction with the Transcription Network for Plant Growth Regulation in Arabidopsis
  - dev cell 19(5):765-777 (2010)
  Brassinosteroids (BRs) regulate a wide range of developmental and physiological processes in plants through a receptor-kinase signaling pathway that controls the BZR transcription factors. Here, we use transcript profiling and chromatin-immunoprecipitation microarray (ChIP-chip) experiments to identify 953 BR-regulated BZR1 target (BRBT) genes. Functional studies of selected BRBTs further demonstrate roles in BR promotion of cell elongation. The BRBT genes reveal numerous molecular links between the BR-signaling pathway and downstream components involved in developmental and physiological processes. Furthermore, the results reveal extensive crosstalk between BR and other hormonal and light-signaling pathways at multiple levels. For example, BZR1 not only controls the expression of many signaling components of other hormonal and light pathways but also coregulates common target genes with light-signaling transcription factors. Our results provide a genomic map of steroi! d hormone actions in plants that reveals a regulatory network that integrates hormonal and light-signaling pathways for plant growth regulation.
• Interplay between the Transcription Factor Zif and aPKC Regulates Neuroblast Polarity and Self-Renewal
  - dev cell 19(5):778-785 (2010)
  How a cell decides to self-renew or differentiate is a critical issue in stem cell and cancer biology. Atypical protein kinase C (aPKC) promotes self-renewal of Drosophila larval brain neural stem cells, neuroblasts. However, it is unclear how aPKC cortical polarity and protein levels are regulated. Here, we have identified a zinc-finger protein, Zif, which is required for the expression and asymmetric localization of aPKC. aPKC displays ectopic cortical localization with upregulated protein levels in dividing zif mutant neuroblasts, leading to neuroblast overproliferation. We show that Zif is a transcription factor that directly represses aPKC transcription. We further show that Zif is phosphorylated by aPKC both in vitro and in vivo. Phosphorylation of Zif by aPKC excludes it from the nucleus, leading to Zif inactivation in neuroblasts. Thus, reciprocal repression between Zif and aPKC act as a critical regulatory mechanism for establishing cell polarity and controlli! ng neuroblast self-renewal.