Hot off the presses! Jul 21 Dev Cell

The Jul 21 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:

• A Receptor for Eating Mitochondria
  - Dev Cell 17(1):1-2 (2009)
  Mitochondria play central roles in cell survival by producing energy, and in cell death by regulating apoptosis. Conversely, the life and death of mitochondria, including growth, fission, and autophagic degradation, is controlled by the host cell. Using yeast genetics, a mitochondrial surface receptor involved in mitochondrial autophagy has recently been identified.
• Cell Size Control: Governed by a Spatial Gradient
  - Dev Cell 17(1):3-4 (2009)
  The phenomenon of cell size homeostasis, whereby cells coordinate growth and division to maintain a uniform cell size, has been an outstanding issue in cell biology for many decades. Two recent studies in Nature in fission yeast demonstrate that a gradient of the polarity factor Pom1 is a sensor of cell length that determines the onset of Cdc2 activation and mitosis.
• Memory of Fate and Position, Colorized
  - Dev Cell 17(1):5-6 (2009)
  Many of our ideas about cellular memory of fate and position come from regeneration studies in salamanders. A popular notion is that cells of the blastema transdifferentiate to different fates during limb regeneration. In a recent issue of Nature, Tanaka and colleagues challenge this notion. Using transplant experiments with GFP-expressing axolotl, they show vividly which cells of the blastema remember their fate and position of origin.
• TGF-β: A New Role for an Old AktTOR
  - Dev Cell 17(1):6-8 (2009)
  Nutrient overabundance is known to promote cellular hypertrophy, a significant pathological event in diseases like diabetes and cancer, although mechanisms have remained unclear. In this issue of Developmental Cell, Wu and Derynck provide a new model that links metabolism and cell growth by demonstrating that hyperglycemia can increase TGF-β-dependent activation of the mTOR pathway to promote cellular hyperplasia.
• Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases
  - Dev Cell 17(1):9-26 (2009)
  Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator β-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate β-catenin stability, from Wnt receptors to the cytoplasmic β-catenin destruction complex, and nuclear machinery that mediates β-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/β-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.
• A New Look at TCF and β-Catenin through the Lens of a Divergent C. elegans Wnt Pathway
  - Dev Cell 17(1):27-34 (2009)
  The canonical Wnt/β-catenin pathway is extensively characterized, broadly conserved, and clinically important. In this review, we describe the C. elegans Wnt/β-catenin asymmetry pathway and suggest that some of its unusual features may have important implications for the canonical Wnt/β-catenin pathway.
• Essential Role of TGF-β Signaling in Glucose-Induced Cell Hypertrophy
  - Dev Cell 17(1):35-48 (2009)
  In multicellular organisms, cell size is tightly controlled by nutrients and growth factors. Increasing ambient glucose induces enhanced protein synthesis and cell size. Continued exposure of cells to high glucose in vivo, as apparent under pathological conditions, results in cell hypertrophy and tissue damage. We demonstrate that activation of TGF-β signaling has a central role in glucose-induced cell hypertrophy in fibroblasts and epithelial cells. Blocking the kinase activity of the TβRI receptor or loss of its expression prevented the effects of high glucose on protein synthesis and cell size. Exposure of cells to high glucose induced a rapid increase in cell surface levels of the TβRI and TβRII receptors and a rapid activation of TGF-β ligand by matrix metalloproteinases, including MMP-2 and MMP-9. The consequent autocrine TGF-β signaling in response to glucose led to Akt-TOR pathway activation. Accordingly, preventing MMP-2/MMP-9 or TGF-β-induced TOR activ! ation inhibited high glucose-induced cell hypertrophy.
• Reciprocal Requirements for EDA/EDAR/NF-κB and Wnt/β-Catenin Signaling Pathways in Hair Follicle Induction
  - Dev Cell 17(1):49-61 (2009)
  Wnt/β-catenin and NF-κB signaling mechanisms provide central controls in development and disease, but how these pathways intersect is unclear. Using hair follicle induction as a model system, we show that patterning of dermal Wnt/β-catenin signaling requires epithelial β-catenin activity. We find that Wnt/β-catenin signaling is absolutely required for NF-κB activation, and that Edar is a direct Wnt target gene. Wnt/β-catenin signaling is initially activated independently of EDA/EDAR/NF-κB activity in primary hair follicle primordia. However, Eda/Edar/NF-κB signaling is required to refine the pattern of Wnt/β-catenin activity, and to maintain this activity at later stages of placode development. We show that maintenance of localized expression of Wnt10b and Wnt10a requires NF-κB signaling, providing a molecular explanation for the latter observation, and identify Wnt10b as a direct NF-κB target. These data reveal a complex interplay and interdependence of Wn! t/β-catenin and EDA/EDAR/NF-κB signaling pathways in initiation and maintenance of primary hair follicle placodes.
• Sox17 Regulates Organ Lineage Segregation of Ventral Foregut Progenitor Cells
  - Dev Cell 17(1):62-74 (2009)
  The ventral pancreas, biliary system, and liver arise from the posterior ventral foregut, but the cell-intrinsic pathway by which these organ lineages are separated is not known. Here we show that the extrahepatobiliary system shares a common origin with the ventral pancreas and not the liver, as previously thought. These pancreatobiliary progenitor cells coexpress the transcription factors PDX1 and SOX17 at E8.5 and their segregation into a PDX1+ ventral pancreas and a SOX17+ biliary primordium is Sox17-dependent. Deletion of Sox17 at E8.5 results in the loss of biliary structures and ectopic pancreatic tissue in the liver bud and common duct, while Sox17 overexpression suppresses pancreas development and promotes ectopic biliary-like tissue throughout the PDX1+ domain. Restricting SOX17+ biliary progenitor cells to the ventral region of the gut requires the notch effector Hes1. Our results highlight the role of Sox17 and Hes1 in patterning and morphogenetic segregati! on of ventral foregut lineages.
• Arabidopsis DOF Transcription Factors Act Redundantly to Reduce CONSTANS Expression and Are Essential for a Photoperiodic Flowering Response
  - Dev Cell 17(1):75-86 (2009)
  Flowering of Arabidopsis is induced by long summer days (LDs). The transcriptional regulator CONSTANS (CO) promotes flowering, and its transcription is increased under LDs. We systematically misexpressed transcription factors in companion cells and identified several DOF proteins that delay flowering by repressing CO transcription. Combining mutations in four of these, including CYCLING DOF FACTOR 2 (CDF2), caused photoperiod-insensitive early flowering by increasing CO mRNA levels. CO transcription is promoted to differing extents by GIGANTEA (GI) and the F-box protein FKF1. We show that GI stabilizes FKF1, thereby reducing CDF2 abundance and allowing transcription of CO. Despite the crucial function of GI in wild-type plants, introducing mutations in the four DOF-encoding genes into gi mutants restored the diurnal rhythm and light inducibility of CO. Thus, antagonism between GI and DOF transcription factors contributes to photoperiodic flowering by modulating an unde! rlying diurnal rhythm in CO transcript levels.
• Mitochondria-Anchored Receptor Atg32 Mediates Degradation of Mitochondria via Selective Autophagy
  - Dev Cell 17(1):87-97 (2009)
  Mitochondria are essential organelles that produce most of the energy for a cell, but concomitantly accumulate oxidative damage. Degradation of damaged mitochondria is critical for cell homeostasis, and this process is thought to be mediated by mitophagy, an autophagy-related pathway specific for mitochondria. However, whether mitochondria are selectively degraded, and how the autophagic machinery is targeted to mitochondria, remain largely unknown. Here we demonstrate that, in post-log phase cells under respiratory conditions, a substantial fraction of mitochondria are exclusively sequestered as cargoes and transported to the vacuole, a lytic compartment in yeast, in an autophagy-dependent manner. Interestingly, we found Atg32, a mitochondria-anchored protein essential for mitophagy that is induced during respiratory growth. In addition, our data suggest that Atg32 interacts with Atg8 and Atg11, autophagy-related proteins critical for recognition of cargo receptors. W! e propose that Atg32 acts as a mitophagy-specific receptor and regulates selective degradation of mitochondria.
• Atg32 Is a Mitochondrial Protein that Confers Selectivity during Mitophagy
  - Dev Cell 17(1):98-109 (2009)
  Mitochondrial quality control is important in maintaining proper cellular homeostasis. Although selective mitochondrial degradation by autophagy (mitophagy) is suggested to have an important role in quality control, and though there is evidence for a direct relation between mitophagy and neurodegenerative diseases, the molecular mechanism of mitophagy is poorly understood. Using a screen for mitophagy-deficient mutants, we found that YIL146C/ECM37 is essential for mitophagy. This gene is not required for other types of selective autophagy or for nonspecific macroautophagy. We designated this autophagy-related (ATG) gene as ATG32. The Atg32 protein localizes on mitochondria. Following the induction of mitophagy, Atg32 binds Atg11, an adaptor protein for selective types of autophagy, and is then recruited to and imported into the vacuole along with mitochondria. Therefore, Atg32 confers selectivity for mitochondrial sequestration as a cargo and is necessary for recruitme! nt of this organelle by the autophagy machinery for mitophagy.
• The Retromer Coat Complex Coordinates Endosomal Sorting and Dynein-Mediated Transport, with Carrier Recognition by the trans-Golgi Network
  - Dev Cell 17(1):110-122 (2009)
  Early endosome-to-trans-Golgi network (TGN) transport is organized by the retromer complex. Consisting of cargo-selective and membrane-bound subcomplexes, retromer coordinates sorting with membrane deformation and carrier formation. Here, we describe four mammalian retromers whose membrane-bound subcomplexes contain specific combinations of the sorting nexins (SNX), SNX1, SNX2, SNX5, and SNX6. We establish that retromer requires a dynamic spatial organization of the endosomal network, which is regulated through association of SNX5/SNX6 with the p150glued component of dynactin, an activator of the minus-end directed microtubule motor dynein; an association further defined through genetic studies in C. elegans. Finally, we also establish that the spatial organization of the retromer pathway is mediated through the association of SNX1 with the proposed TGN-localized tether Rab6-interacting protein-1. These interactions describe fundamental steps in retromer-mediated trans! port and establish that the spatial organization of the retromer network is a critical element required for efficient retromer-mediated sorting.
• miR-184 Has Multiple Roles in Drosophila Female Germline Development
  - Dev Cell 17(1):123-133 (2009)
  Posttranscriptional regulation plays a crucial role in germline and early embryonic development, but the underlying mechanisms are only partially understood. Here we report the genetic and molecular analysis of the maternally and zygotically expressed microRNA miR-184 in Drosophila. Loss of miR-184 leads to multiple severe defects during oogenesis and early embryogenesis, culminating in the complete loss of egg production. Using both in vitro and in vivo assays, we characterize the relevant miR-184 targets and target sites for three of the observed phenotypes. miR-184 controls germline stem cell differentiation by tuning the DPP receptor Saxophone, dorsoventral patterning of the egg shell by regulating the gurken transport factor K10, and anteroposterior patterning of the blastoderm by tuning the transcriptional repressor Tramtrack69. Our study highlights the importance of microRNA-mediated regulation in the major developmental transitions of the female germline, and p! rovides insights into several aspects of microRNA function.
• Apical/Basal Spindle Orientation Is Required for Neuroblast Homeostasis and Neuronal Differentiation in Drosophila
  - Dev Cell 17(1):134-141 (2009)
  Precise regulation of stem cell self-renewal/differentiation is essential for embryogenesis and tumor suppression. Drosophila neural progenitors (neuroblasts) align their spindle along an apical/basal polarity axis to generate a self-renewed apical neuroblast and a differentiating basal cell. Here, we genetically disrupt spindle orientation without altering cell polarity to test the role of spindle orientation in self-renewal/differentiation. We perform correlative live imaging of polarity markers and spindle orientation over multiple divisions within intact brains, followed by molecular marker analysis of cell fate. We find that spindle alignment orthogonal to apical/basal polarity always segregates apical determinants into both siblings, which invariably assume a neuroblast identity. Basal determinants can all be localized into one sibling without inducing neuronal differentiation, but overexpression of the basal determinant Prospero can deplete neuroblasts. We concl! ude that the ratio of apical/basal determinants specifies neuroblast/GMC identity, and that apical/basal spindle orientation is required for neuroblast homeostasis and neuronal differentiation.
• p38MAPK Controls Expression of Multiple Cell Cycle Inhibitors and Islet Proliferation with Advancing Age
  - Dev Cell 17(1):142-149 (2009)
  Aging is a complex organismal process that is controlled by genetic, environmental, and behavioral factors. Accumulating evidence supports a role for different cell cycle inhibitors in mammalian aging. Little is known, however, about the upstream signals that induce their expression. Here, we explore the role of p38MAPK by generating a dominant-negative allele (p38AF) in which activating phosphorylation sites Thr180 and Tyr182 are mutated. Heterozygous p38AF mice show a marked attenuation of p38-dependent signaling and age-induced expression of multiple cell cycle inhibitors in different organs, including pancreatic islets. As a result, aged p38AF/+ mice show enhanced proliferation and regeneration of islets when compared to wild-type littermates. We further find an age-related reduction in expression of the p38-specific phosphatase Wip1. Wip1-deficient mice demonstrate decreased islet proliferation, while Wip1 overexpression rescues aging-related decline in proliferat! ion and regenerative capacity. We propose that modulation of p38MAPK activity may provide new avenues for treating certain age-related degenerative diseases.
• Distinct Regulatory Cascades Govern Extraocular and Pharyngeal Arch Muscle Progenitor Cell Fates
  - Dev Cell 17(1):150 (2009)