Institute of Molecular Cell Biology

Singapore, Singapore

Institute of Molecular Cell Biology

Singapore, Singapore
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News Article | July 28, 2017
Site: www.newscientist.com

Off with their heads. Light-averse planarian flatworms, known for their incredible ability to regenerate lost body parts, shy away from light even after they have been decapitated. This suggests they have evolved a second way to respond to light that doesn’t involve eyes. Planarian flatworms, which often live in dark, watery environments shielded from direct light, don’t have complex eyes like we do. But many do have two lensless, primitive “eyespots” on their heads that can detect the intensity of light. Akash Gulyani at the Institute for Stem Cell Biology and Regenerative Medicine in Bangalore, India, and his colleagues were curious to find out more about flatworm vision. They studied the species Schmidtea mediterranea, confirming that its eyespots encourage the animals to shy away from visible light. Unexpectedly, it turned out that S. mediterranea actually has colour vision of sorts. Even though its eyespots lack wavelength-specific photoreceptors, Gulyani’s team found that the animal was more likely to move away from blue than red light. The researchers think the worms are distinguishing between different colours by comparing the amount of light being absorbed by the two eyespots, rather than seeing the colour of the light itself: for instance, they could override the flatworm’s preference for red over blue light by increasing the intensity of the former. But there’s much more to flatworm vision than this. Gulyani and his colleagues next exploited the fact that their planarian flatworms can survive decapitation – and regrow their heads – to explore how they respond to light when headless. It turned out that the worms still reacted to light, but in the ultraviolet rather than the visible part of the spectrum. This suggests that the worms have evolved two completely independent ways to respond to light, say the researchers – one mediated through the eyespots and brain, and one a body-wide reflex that doesn’t involve the eyes, the exact mechanism for which still needs to be identified. Over the week-long period it took for the flatworms to regenerate their heads, the team monitored how quickly their brains and eyespots regrew, and when they began responding to visible light again. After four days, the eyespots had grown back, but the worms continued to react more strongly to UV than to visible light. Only after seven days did they regain their stronger preference to slither away from visible light – suggesting that their eyespots and brains were retaking control. It was not until the 12th day that their sensitivity to such light increased to the point that they reacted more strongly to light at the bluer end of the visible spectrum. Gulyani’s team speculates that the “gut instinct” response to UV light may be an ancient mechanism, with the eyespot and brain-controlled response to visible light a later evolutionary acquisition. As such, the researchers wonder whether their experiments might “replay” evolution in fast forward, showing how flatworms went from responding to ultraviolet light as an unthinking reflex to responding to visible light through a brain-controlled pathway. “It’s a fascinating coincidence that decapitation-regeneration experiments appear to copy – chronologically, at least – what may have occurred in evolution,” says Gulyani. It’s an idea that might be worth exploring in future experiments. Jochen Rink at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, thinks the team’s experiment was beautifully designed, and creative in its use of planarians. “Where else in nature can you chop off a head and ask if the rest of the body can see light or not?” he says. Read more: Bioelectric tweak makes flatworms grow a head instead of a tail


Schliekelman M.J.,Fred Hutchinson Cancer Research Center | Taguchi A.,University of Houston | Zhu J.,Mount Sinai School of Medicine | Dai X.,Mount Sinai School of Medicine | And 19 more authors.
Cancer Research | Year: 2015

Epithelial-to-mesenchymal transition (EMT) is a key process associated with tumor progression and metastasis. To define molecular features associated with EMT states, we undertook an integrative approach combining mRNA, miRNA, DNA methylation, and proteomic profiles of 38 cell populations representative of the genomic heterogeneity in lung adenocarcinoma. The resulting data were integrated with functional profiles consisting of cell invasiveness, adhesion, and motility. A subset of cell lines that were readily defined as epithelial or mesenchymal based on their morphology and E-cadherin and vimentin expression elicited distinctive molecular signatures. Other cell populations displayed intermediate/hybrid states of EMT, with mixed epithelial and mesenchymal characteristics. A dominant proteomic feature of aggressive hybrid cell lines was upregulation of cytoskeletal and actin-binding proteins, a signature shared with mesenchymal cell lines. Cytoskeletal reorganization preceded loss of E-cadherin in epithelial cells in which EMT was induced by TGFb. A set of transcripts corresponding to the mesenchymal protein signature enriched in cytoskeletal proteins was found to be predictive of survival in independent datasets of lung adenocarcinomas. Our findings point to an association between cytoskeletal and actinbinding proteins, a mesenchymal or hybrid EMT phenotype and invasive properties of lung adenocarcinomas. Cancer Res; 75(9); 1789-800. © 2015 AACR.


Li Q.,National University of Singapore | Zhang Y.,National University of Singapore | Pluchon P.,National University of Singapore | Robens J.,National University of Singapore | And 7 more authors.
Nature Cell Biology | Year: 2016

The de novo formation of secretory lumens plays an important role during organogenesis. It involves the establishment of a cellular apical pole and the elongation of luminal cavities. The molecular parameters controlling cell polarization have been heavily scrutinized. In particular, signalling from the extracellular matrix (ECM) proved essential to the proper localization of the apical pole by directed protein transport. However, little is known about the regulation of the shape and the directional development of lumen into tubes. We demonstrate that the spatial scaffolding of cells by ECM can control tube shapes and can direct their elongation. We developed a minimal organ approach comprising of hepatocyte doublets cultured in artificial microniches to precisely control the spatial organization of cellular adhesions in three dimensions. This approach revealed a mechanism by which the spatial repartition of integrin-based adhesion can elicit an anisotropic intercellular mechanical stress guiding the osmotically driven elongation of lumens in the direction of minimal tension. This mechanical guidance accounts for the different morphologies of lumen in various microenvironmental conditions. © 2016 Macmillan Publishers Limited.


Gruber R.,Leibniz Institute for Age Research | Gruber R.,Cancer Research UK Research Institute | Zhou Z.,Leibniz Institute for Age Research | Sukchev M.,Leibniz Institute for Age Research | And 4 more authors.
Nature Cell Biology | Year: 2011

Primary microcephaly 1 is a neurodevelopmental disorder caused by mutations in the MCPH1 gene, whose product MCPH1 (also known as microcephalin and BRIT1) regulates DNA-damage response. Here we show that Mcph1 disruption in mice results in primary microcephaly, mimicking human MCPH1 symptoms, owing to a premature switching of neuroprogenitors from symmetric to asymmetric division. MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle. This misorients the mitotic spindle alignment and shifts the division plane of neuroprogenitors, to bias neurogenic cell fate. Silencing Cdc25b, a centrosome substrate of Chk1, corrects MCPH1-deficiency-induced spindle misalignment and rescues the premature neurogenic production in Mcph1-knockout neocortex. Thus, MCPH1, through its function in the Chk1-Cdc25-Cdk1 pathway to couple the centrosome cycle with mitosis, is required for precise mitotic spindle orientation and thereby regulates the progenitor division mode to maintain brain size. © 2011 Macmillan Publishers Limited. All rights reserved.


Lim J.,Institute of Molecular Cell Biology | Thiery J.P.,Institute of Molecular Cell Biology | Thiery J.P.,National University of Singapore
Development (Cambridge) | Year: 2012

Epithelial-mesenchymal transition (EMT) is a crucial, evolutionarily conserved process that occurs during development and is essential for shaping embryos. Also implicated in cancer, this morphological transition is executed through multiple mechanisms in different contexts, and studies suggest that the molecular programs governing EMT, albeit still enigmatic, are embedded within developmental programs that regulate specification and differentiation. As we review here, knowledge garnered from studies of EMT during gastrulation, neural crest delamination and heart formation have furthered our understanding of tumor progression and metastasis. © 2012. Published by The Company of Biologists Ltd.


Hilgers V.,National University of Singapore | Hilgers V.,European Molecular Biology Laboratory | Hilgers V.,Institute of Molecular Cell Biology | Bushati N.,National University of Singapore | And 3 more authors.
PLoS Biology | Year: 2010

MiR-263a/b are members of a conserved family of microRNAs that are expressed in peripheral sense organs across the animal kingdom. Here we present evidence that miR-263a and miR-263b play a role in protecting Drosophila mechanosensory bristles from apoptosis by down-regulating the pro-apoptotic gene head involution defective. Both microRNAs are expressed in the bristle progenitors, and despite a difference in their seed sequence, they share this key common target. In miR-263a and miR263b deletion mutants, loss of bristles appears to be sporadic, suggesting that the role of the microRNAs may be to ensure robustness of the patterning process by promoting survival of these functionally specified cells. In the context of the retina, this mechanism ensures that the interommatidial bristles are protected during the developmentally programmed wave of cell death that prunes excess cells in order to refine the pattern of the pupal retina. © 2010 Hilgers et al.


Zhang W.,Institute of Molecular Cell Biology | Cohen S.M.,Institute of Molecular Cell Biology | Cohen S.M.,National University of Singapore
Biology Open | Year: 2013

The Hippo pathway has a central role in coordinating tissue growth and apoptosis. Mutations that compromise Hippo pathway activity cause tissue overgrowth and have been causally linked to cancer. In Drosophila, the transcriptional coactivator Yorkie mediates Hippo pathway activity to control the expression of cyclin E and Myc to promote cell proliferation, as well as the expression of bantam miRNA and DIAP1 to inhibit cell death. Here we present evidence that the Hippo pathway acts via Yorkie and p53 to control the expression of the proapoptotic gene reaper. Yorkie further mediates reaper levels posttranscriptionally through regulation of members of the miR-2 microRNA family to prevent apoptosis. These findings provide evidence that the Hippo pathway acts via several distinct routes to limit proliferation-induced apoptosis. © 2013. Published by The Company of Biologists Ltd.


PubMed | Singapore Institute of Medical Biology, National University of Singapore and Institute of Molecular & Cell Biology
Type: Journal Article | Journal: The Biochemical journal | Year: 2016

PAKs (p21 activated kinases) are an important class of Rho effectors. These contain a Cdc42-Rac1 interaction and binding (CRIB) domain and a flanking auto-inhibitory domain (AID) which binds the C-terminal catalytic domain. The group II kinases PAK4 and PAK5 are considered significant therapeutic targets in cancer. Among human cancer cell lines we tested, PAK5 protein levels are much lower than those of PAK4, even in NCI-H446 which has the highest PAK5 mRNA expression. Although these two kinases are evolutionarily and structurally related, it has never been established why PAK4 is inactive whereas PAK5 has high basal activity. The AID of PAK5 is functionally indistinguishable from that of PAK4, pointing to other regions being responsible for higher activity of PAK5. Gel filtration indicates PAK4 is a monomer but PAK5 is dimeric. The central region of PAK5 (residues 109-420) is shown here to promote self-association, and an elevated activity, but has no effect on activation loop Ser(602) phosphorylation. These residues allow PAK5 to form characteristic puncta in cells, and removing sequences involved in oligomerization suppresses kinase activity. Our model suggests PAK5 self-association interferes with AID binding to the catalytic domain, thus maintaining its high activity. Further, our model explains the observation that PAK5 (1-180) inhibits PAK5 invitro.


Sakry D.,Institute of Molecular Cell Biology | Trotter J.,Institute of Molecular Cell Biology
Brain Research | Year: 2015

In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). © 2015 Elsevier B.V.


News Article | December 15, 2016
Site: www.chromatographytechniques.com

An international research team comprised of six evolutionary biologists sequenced the full genome of a tiger tail seahorse, or Hippocampus comes, for the first time. The world’s oceans are filled with a variety of bizarre and wild organisms, and the seahorse certainly tops the list. For starters, the fish doesn’t physically resemble any other type of fish. The seahorse’s body stands vertical, not horizontal like traditional fish and in lieu of scales or ribs, it has boney plates that act as a shield of defense against predators. Seahorses also lack a pelvic fin, which is essentially the equivalent of not having hind legs. Instead, they navigate through the water by fluttering their unique curled tail up to 30 times per second. And without teeth, the fish uses suction through its tubular mouth to eat. Seahorses are the only known vertebrate to exhibit male pregnancy, as well. Female seahorses are tough to impress, so the males perform an elaborate courting dance, which can last as long as a few days. Once the female is wooed, she transfers more than 1,000 eggs into the male’s pouch through an organ specifically designed for this task. The male fertilizes the eggs and ensures the embryos grow safely in his pouch, just like a mother of any other species would do. When the embryos are ready, the male will begin to feel contractions and actually push the embryos out of the pouch. The babies are on their own from there, and the male wastes no time in starting the process over again. All of these fascinating traits evolved over a very short period of time, further intriguing scientists to learn more. So a team, led by Byrappa Venkatesh of the Institute of Molecular Cell Biology in Singapore, sequenced the full genome of a tiger tail seahorse and published the initial results as the cover story in Nature on Dec. 15. The team chose the tiger tail out of the 47 known species of seahorses because they can be found in abundance near Singapore, where the research was conducted. The researchers already knew that the seahorse lineage diverted from other fish more than 100 million years ago during the Cretaceous period, but by analyzing the fish’s full genome, they can provide answers to questions about the unique traits and mating behaviors that are currently still a mystery, and find out how they are being expressed at the genetic level. One of the initial key discoveries the researchers reported on was that the genome is missing a set of genes responsible for coding enamel, which explains why seahorses don’t have teeth and have to “suck” their food. Another gene loss noted was the lack of tbx4, which regulates growth of pelvic fins and is found in nearly all other vertebrates. The researchers tested the function of this gene by using zebrafish as a model. The team deactivated the tbx4 gene via the CRISPR-cas method and saw that the zebrafish then also lost their pelvic fins, proving the importance of that specific gene in regular pelvic fin development. While the tiger tail seahorse lacks genes crucial to survival for other species, it has six copies of the Pastrisacin gene, which is linked with male pregnancy. According to the researchers, proteins and DNA in seahorses have evolved much faster than their closest cousins, such as pipe fish and sea dragons, but the researchers don’t yet know why. They will be able to get an even better understanding of the peculiarities of the seahorse by comparing the tiger tail genome with other seahorse species, as well as its closest relatives.

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