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Lin C.-Y.,National Tsing Hua University | Chuang C.-C.,National Center for High Performance Computing | Chuang C.-C.,National Chiao Tung University | Hua T.-E.,National Tsing Hua University | And 6 more authors.
Cell Reports | Year: 2013

How the brain perceives sensory information and generates meaningful behavior depends critically on its underlying circuitry. The protocerebral bridge (PB) is a major part of the insect central complex (CX), a premotor center that may be analogous to the human basal ganglia. Here, by deconstructing hundreds of PB single neurons and reconstructing them into a common three-dimensional framework, we have constructed a comprehensive map of PB circuits with labeled polarity and predicted directions of information flow. Our analysis reveals a highly ordered information processing system that involves directed information flow among CX subunits through 194 distinct PB neuron types. Circuitry properties such as mirroring, convergence, divergence, tiling, reverberation, and parallel signal propagation were observed; their functional and evolutional significance is discussed. This layout of PB neuronal circuitry may provide guidelines for further investigations on transformation of sensory (e.g., visual) input into locomotor commands in fly brains. © 2013 The Authors.

Schmitz M.H.A.,ETH Zurich | Schmitz M.H.A.,National Oceanic and Atmospheric Administration | Schmitz M.H.A.,University of Zürich | Held M.,ETH Zurich | And 15 more authors.
Nature Cell Biology | Year: 2010

When vertebrate cells exit mitosis various cellular structures are re-organized to build functional interphase cells. This depends on Cdk1 (cyclin dependent kinase 1) inactivation and subsequent dephosphorylation of its substrates. Members of the protein phosphatase 1 and 2A (PP1 and PP2A) families can dephosphorylate Cdk1 substrates in biochemical extracts during mitotic exit, but how this relates to postmitotic reassembly of interphase structures in intact cells is not known. Here, we use a live-cell imaging assay and RNAi knockdown to screen a genome-wide library of protein phosphatases for mitotic exit functions in human cells. We identify a trimeric PP2A-B55α complex as a key factor in mitotic spindle breakdown and postmitotic reassembly of the nuclear envelope, Golgi apparatus and decondensed chromatin. Using a chemically induced mitotic exit assay, we find that PP2A-B55α functions downstream of Cdk1 inactivation. PP2A-B55α isolated from mitotic cells had reduced phosphatase activity towards the Cdk1 substrate, histone H1, and was hyper-phosphorylated on all subunits. Mitotic PP2A complexes co-purified with the nuclear transport factor importin-β 21, and RNAi depletion of importin-β 21 delayed mitotic exit synergistically with PP2A-B55α. This demonstrates that PP2A-B55α and importin-β 21 cooperate in the regulation of postmitotic assembly mechanisms in human cells.

Lauwers M.,Institute of Molecular Pathology | Pichler P.,Institute of Molecular Pathology | Edelman N.B.,Institute of Molecular Pathology | Resch G.P.,Campus Science Support Facilities | And 6 more authors.
Current Biology | Year: 2013

Hair cells reside in specialized epithelia in the inner ear of vertebrates, mediating the detection of sound, motion, and gravity. The transduction of these stimuli into a neuronal impulse requires the deflection of stereocilia, which are stabilized by the actin-rich cuticular plate. Recent electrophysiological studies have implicated the vestibular system in pigeon magnetosensation [1]. Here we report the discovery of a single iron-rich organelle that resides in the cuticular plate of cochlear and vestibular hair cells in the pigeon. Transmission electron microscopy, coupled with elemental analysis, has shown that this structure is composed of ferritin-like granules, is approximately 300-600 nm in diameter, is spherical, and in some instances is membrane-bound and/or organized in a paracrystalline array. This organelle is found in hair cells in a wide variety of avian species, but not in rodents or in humans. This structure may function as (1) a store of excess iron, (2) a stabilizer of stereocilia, or (3) a mediator of magnetic detection. Given the specific subcellular location, elemental composition, and evolutionary conservation, we propose that this structure is an integral component of the sensory apparatus in birds. © 2013 Elsevier Ltd.

News Article | November 18, 2015
Site: www.nature.com

In the cells of fruit flies, Chinese scientists say that they have found a biological compass needle: a rod-shaped complex of proteins that can align with Earth’s weak magnetic field. The biocompass — whose constituent proteins exist in related forms in other species, including humans — could explain a long-standing puzzle: how animals such as birds and insects sense magnetism. It might also become an invaluable tool for using magnetic fields to control cells, report researchers led by biophysicist Xie Can at Peking University in Beijing, in a paper published on 16 November in Nature Materials (S. Qin et al. Nature Mater. http://dx.doi.org/10.1038/nmat4484; 2015). “It’s an extraordinary paper,” says Peter Hore, a biochemist at the University of Oxford, UK. But Xie’s team has not shown that the complex actually behaves as a biocompass inside living cells, nor explained exactly how it senses magnetism. “It’s either a very important paper or totally wrong. I strongly suspect the latter,” says David Keays, a neuroscientist who studies magnetoreception at the Institute of Molecular Pathology in Vienna. Many organisms — ranging from whales to butterflies, and termites to pigeons — use Earth’s magnetic field to navigate or orient themselves in space. But the molecular mechanism behind this ability, termed magneto-reception, is unclear. Some researchers have pointed to magnetically sensitive proteins called ‘cryptochromes’, or ‘Cry’. Fruit flies lacking the proteins lose their sensitivity to magnetic fields, for example. But the Cry proteins alone cannot act as a compass, says Xie, because they cannot sense the polarity (north–south orientation) of magnetic fields. Others have suggested that iron-based minerals might be responsible. Magnetite, a form of iron oxide, has been found in the beak cells of homing pigeons. Yet studies suggest that magnetite plays no part in pigeon magnetoreception. Xie says that he has found a protein in fruit flies that both binds to iron and interacts with Cry. Known as CG8198, it binds iron and sulfur atoms and is involved in fruit-fly circadian rhythms. Together with Cry, it forms a nanoscale ‘needle’: a rod-like core of CG8198 polymers with an outer layer of Cry proteins that twists around the core (see 'Protein biocompass'). Using an electron microscope, Xie’s team saw assemblies of these rods orienting themselves in a weak magnetic field in the same way as compass needles. Xie gave CG8198 the new name of MagR, for magnetic receptor. The discovery offers scientists the prospect of using magnetic fields to control cells. Over the past decade, scientists have commandeered the light-sensing capacity of some proteins to manipulate neurons, usually by inserting a fibre-optic cable directly into the brain — a tool called optogenetics. But magnetosensing proteins have the advantage that they could be manipulated by magnetic fields outside the brain. Zhang Sheng-jia, a neuroscientist at Tsinghua University in Beijing, claims to have already demonstrated this ‘magnetogenetic’ capability. In September, he provided a surprise preview of Xie’s work when he published a paper reporting use of the biocompass to manipulate neurons in worms (X. Long et al. Sci. Bull. http://doi.org/883; 2015). Xie and others complained that Zhang’s early publication violated a collaboration agreement between the two researchers — the details of which are disputed — and asked for it to be retracted. In October, Zhang was fired from his university, a decision that he is contesting. Xie says that in April, he submitted a Chinese patent application that includes the use of magnetogenetics and the protein’s magnetic capacity to manipulate large molecules. He is also starting to look at the structure of MagR proteins in other animals, including humans. Variants in the human version of MagR might even relate to differences in people’s sense of direction, he suggests. Other scientists are not convinced that the biological needles function like compasses in living organisms. Xie’s team has shown that MagR and Cry are produced in the same cells in pigeon retinas — the birds’ proposed magnetoreception centre — but MagR and Cry are found in many cells, says Keays. “With such a small amount of iron, one has to ask whether in vivo, at physiological temperatures, MagR is capable of possessing magnetic properties at all,” he says. “If MagR is the real magnetoreceptor, I’ll eat my hat.” Xie  hopes that others will strengthen his case with further experiments, such as inactivating the gene for MagR in certain fruit-fly tissues to see whether it affects the animals’ sense of direction. He published without doing this work, he says, because he just wanted to report the findings, which he has been working on for six years. The lack of an exact mechanism for how the protein complex senses magnetism, or how any signal it sends might be processed by the brain, gives some researchers pause. MagR’s biocompass activity might simply be the result of experimental contamination, says Michael Winklhofer, a magnetism specialist and Earth scientist at Ludwig Maximilian University of Munich in Germany. He is planning experiments to follow up on Xie’s team’s findings. If it holds up, says Winklhofer, then the discovery of MagR “appears to be a major step forward towards unravelling the molecular basis of magnetoreception”.

Wang Q.,Rockefeller University | Oliveira T.,Rockefeller University | Jankovic M.,Rockefeller University | Silva I.T.,Rockefeller University | And 11 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation (SHM) by deaminating cytosine residues in immunoglobulin genes (Igh, Igκ, and Igλ). At a lower frequency, AID also causes collateral DNA damage at non-Ig loci, including genes that are rearranged or mutated in B-cell lymphoma. Precisely how AID is recruited to these off-target sites is not entirely understood. To gain further insight into how AID selects its targets, we compared AID-mediated translocations in two different cell types, B cells and mouse embryonic fibroblasts (MEFs). AID targets a distinct set of hotspots in the two cell types. In both cases, hotspots are concentrated in highly transcribed but stalled genes. However, transcription alone is insufficient to recruit AID activity. Comparison of genes similarly transcribed in B cells and MEFs but targeted in only one of the two cell types reveals a common set of epigenetic features associated with AID recruitment in both cells. AID target genes are enriched in chromatin modifications associated with active enhancers (such as H3K27Ac) and marks of active transcription (such as H3K36me3) in both fibroblasts and B cells, indicating that these features are universal mediators of AID recruitment. © 2014, National Academy of Sciences. All rights reserved.

Kramer J.M.,Radboud University Nijmegen | Kochinke K.,Radboud University Nijmegen | Oortveld M.A.W.,Radboud University Nijmegen | Marks H.,Radboud University Nijmegen | And 11 more authors.
PLoS Biology | Year: 2011

The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the "writers" of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5′ and 3′ ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease. © 2011 Kramer et al.

Kudithipudi S.,University of Stuttgart | Lungu C.,University of Stuttgart | Rathert P.,Jacobs University Bremen | Rathert P.,Institute of Molecular Pathology | And 2 more authors.
Chemistry and Biology | Year: 2014

The nuclear receptor binding SET [su(var) 3-9, enhancer of zeste, trithorax] domain-containing protein 1 (NSD1) protein lysine methyltransferase (PKMT) was known to methylate histone H3 lysine 36 (H3K36). We show here that NSD1 prefers aromatic, hydrophobic, and basic residues at the -2, -1 and +2, and +1 sites of its substrate peptide, respectively. We show methylation of 25 nonhistone peptide substrates by NSD1, two of which were (weakly) methylated at the protein level, suggesting that unstructured protein regions are preferred NSD1 substrates. Methylation of H4K20 and p65 was not observed. We discovered strong methylation of H1.5 K168, which represents the best NSD1 substrate protein identified so far, and methylation of H4K44 which was weaker than H3K36. Furthermore, we show that Sotos mutations in the SET domain of NSD1 inactivate the enzyme. Our results illustrate the importance of specificity analyses of PKMTs for understanding protein lysine methylation signaling pathways. © 2014 Elsevier Ltd. All rights reserved.

Maier H.J.,University of Ulm | Wirth T.,University of Ulm | Beug H.,Institute of Molecular Pathology
Cancers | Year: 2010

Pancreatic carcinoma is the fourth-leading cause of cancer death and is characterized by early invasion and metastasis. The developmental program of epithelial-mesenchymal transition (EMT) is of potential importance for this rapid tumor progression. During EMT, tumor cells lose their epithelial characteristics and gain properties of mesenchymal cells, such as enhanced motility and invasive features. This review will discuss recent findings pertinent to EMT in pancreatic carcinoma. Evidence for and molecular characteristics of EMT in pancreatic carcinoma will be outlined, as well as the connection of EMT to related topics, e.g., cancer stem cells and drug resistance. © 2010 by the authors; licensee MDPI, Basel, Switzerland.

Breuss M.,Institute of Molecular Pathology | Keays D.A.,Institute of Molecular Pathology
Advances in experimental medicine and biology | Year: 2014

The development of the mammalian cortex requires the generation, migration and differentiation of neurons. Each of these cellular events requires a dynamic microtubule cytoskeleton. Microtubules are required for interkinetic nuclear migration, the separation of chromatids in mitosis, nuclear translocation during migration and the outgrowth of neurites. Their importance is underlined by the finding that mutations in a host of microtubule associated proteins cause detrimental neurological disorders. More recently, the structural subunits of microtubules, the tubulin proteins, have been implicated in a spectrum of human diseases collectively known as the tubulinopathies. This chapter reviews the discovery of microtubules, the role they play in neurodevelopment, and catalogues the tubulin isoforms associated with neurodevelopmental disease. Our focus is on the molecular and cellular mechanisms that underlie the pathology of tubulin-associated diseases. Finally, we reflect on whether different tubulin genes have distinct intrinsic functions.

Lyashenko N.,Institute of Molecular Pathology | Weissenbock M.,Institute of Molecular Pathology | Sharir A.,Weizmann Institute of Science | Erben R.G.,University of Veterinary Medicine Vienna | And 2 more authors.
Developmental Dynamics | Year: 2010

Ror1 is a member of the Ror-family receptor tyrosine kinases. Ror1 is broadly expressed in various tissues and organs during mouse embryonic development. However, so far little is known about its function. The closely related family member Ror2 was shown to play a crucial role in skeletogenesis and has been shown to act as a co-receptor for Wnt5a mediating non-canonical Wnt-signaling. Previously, it has been shown that during embryonic development Ror1 acts in part redundantly with Ror2 in the skeletal and cardiovascular systems. In this study, we report that loss of the orphan receptor Ror1 results in a variety of phenotypic defects within the skeletal and urogenital systems and that Ror1 mutant mice display a postnatal growth retardation phenotype. © 2010 Wiley-Liss, Inc.

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