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Rizzo F.,Stazione Zoologica Anton Dohrn | Rizzo F.,University of Salerno | Coffman J.A.,MDI Biological Laboratory | Arnone M.I.,Stazione Zoologica Anton Dohrn
Developmental Biology | Year: 2016

Elk proteins are Ets family transcription factors that regulate cell proliferation, survival, and differentiation in response to ERK (extracellular-signal regulated kinase)-mediated phosphorylation. Here we report the embryonic expression and function of Sp-Elk, the single Elk gene of the sea urchin Strongylocentrotus purpuratus. Sp-Elk is zygotically expressed throughout the embryo beginning at late cleavage stage, with peak expression occurring at blastula stage. Morpholino antisense-mediated knockdown of Sp-Elk causes blastula-stage developmental arrest and embryo disintegration due to apoptosis, a phenotype that is rescued by wild-type Elk mRNA. Development is also rescued by Elk mRNA encoding a serine to aspartic acid substitution (S402D) that mimics ERK-mediated phosphorylation of a conserved site that enhances DNA binding, but not by Elk mRNA encoding an alanine substitution at the same site (S402A). This demonstrates both that the apoptotic phenotype of the morphants is specifically caused by Elk depletion, and that phosphorylation of serine 402 of Sp-Elk is critical for its anti-apoptotic function. Knockdown of Sp-Elk results in under-expression of several regulatory genes involved in cell fate specification, cell cycle control, and survival signaling, including the transcriptional regulator Sp-Runt-1 and its target Sp-PKC1, both of which were shown previously to be required for cell survival during embryogenesis. Both Sp-Runt-1 and Sp-PKC1 have sequences upstream of their transcription start sites that specifically bind Sp-Elk. These results indicate that Sp-Elk is the signal-dependent activator of a feed-forward gene regulatory circuit, consisting also of Sp-Runt-1 and Sp-PKC1, which actively suppresses apoptosis in the early embryo. © 2016 Elsevier Inc.

News Article | February 16, 2017

BAR HARBOR, MAINE -- Scientists have known for decades that drastically restricting certain nutrients without causing malnutrition prolongs health and lifespan in a wide range of species, but the molecular mechanisms underlying this effect have remained a mystery. In a paper recently published in the journal Aging Cell, MDI Biological Laboratory scientist Aric Rogers, Ph.D., sheds light on an important genetic pathway underlying this process, raising the possibility that therapies can be developed that prolong the healthy years without having to suffering the consequences of a severely restricted diet. "It's tantalizing to think that we might be able to activate a protective response to enhance our own health without resorting to extreme dietary regimes," Rogers said. Rogers studies mechanisms important to the positive effects of dietary restriction in an intact organism -- the tiny roundworm, C. elegans -- as opposed to cells in a petri dish. C. elegans is an important model in aging research because it shares nearly half of its genes with humans and because of its short lifespan -- it lives for only two to three weeks -- which allows scientists to study many generations over a short period of time. "Aric's identification of a molecular mechanism governing the life-prolonging effects of dietary restriction is a validation of our unique approach to research in aging and regenerative biology," said Kevin Strange, Ph.D., president of the MDI Biological Laboratory. "Our use of whole organisms as research models provides greater insight into the many factors controlling physiological processes than the use of cells alone." Rogers studies the molecular mechanisms underlying aging at the MDI Biological Laboratory's Kathryn W. Davis Center for Regenerative Biology and Medicine. The laboratory is an independent, non-profit biomedical research institution located in Bar Harbor, Maine, focused on increasing healthy lifespan and increasing the body's natural ability to repair and regenerate tissues damaged by injury or disease. The life-prolonging effects of dietary restriction, also known as DR or CR (calorie restriction), occur in just about every animal tested. They are thought to be an evolutionary adaptation to harsh environmental conditions. In the absence of enough food to eat, evolution has programmed organisms to switch from a growth mode to a survival mode so they can live long enough to reproduce when conditions improve. The new study builds on Rogers' earlier research linking the effects of DR to the inhibition of genes governing the formation of proteins. In times of hardship, the body cuts back on the bulk of proteins synthesized, which are linked with growth and reproduction, in order to redirect the cell's energy toward stress-responsive proteins that help extend lifespan by maintaining cell balance and health. Specifically, the study found that the enhanced robustness associated with reducing the production of protein isn't from reduced protein synthesis per se, rather to the triggering of a stress response governing protein homeostasis -- or proteostasis -- a fancy word for the cell's quality control machinery. The stress response ensures that this quality control machinery keeps working optimally, despite harsh environmental conditions. The cell's quality control machinery is responsible for ensuring that newly synthesized proteins are properly shaped and that damaged proteins are quickly destroyed. Misshapen and damaged proteins can interfere with cell function, leading to disease and death. The identification of a mechanism underlying the protective effect of DR could lead to therapies for age-related diseases, including Alzheimer's and Parkinson's, that are associated with diminished cellular quality control. Alzheimer's, for instance, is associated with the build-up of a toxic protein, beta amyloid, in the brain, and Parkinson's with a build-up of a toxic protein called alpha synuclein. The link between aging and weakened cellular "housekeeping" functions raises the possibility that new drugs to prolong lifespan could also delay the onset of age-related degenerative diseases. Now that Rogers has identified a link, the next step is to investigate cause and effect by manipulating the genetic pathways that inhibit protein formation to see if the body's ability to clear molecular clutter is improved. "We think therapies to activate these protective pathways could not only prolong lifespan, but also delay the onset of age-related diseases," Rogers said. "Most older people suffer from multiple chronic diseases. Anti-aging procedures applied to disease models almost always delay disease onset and improve outcomes, which suggests that disease-suppressing benefits may be accessed to extend healthy human lifespan." Our scientists are pioneering new approaches to regenerative medicine focused on drugs that activate our natural ability to heal, and that slow age-related degenerative changes. Our unique approach has identified new drugs with the potential to treat major diseases, demonstrating that regeneration could be as simple as taking a pill. As innovators and entrepreneurs, we also teach what we know. Our new Center for Science Entrepreneurship prepares students for 21st century careers and equips entrepreneurs with the skills and resources to turn great ideas into successful products. For more information, please visit

Henter H.J.,University of California at San Diego | Imondi R.,Coastal Marine Biolabs | James K.,MDI Biological Laboratory | Spencer D.,Tulsa Community College | Steinke D.,University of Guelph
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Despite 250 years of modern taxonomy, there remains a large biodiversity knowledge gap. Most species remain unknown to science. DNA barcoding can help address this gap and has been used in a variety of educational contexts to incorporate original research into school curricula and informal education programmes. A growing body of evidence suggests that actively conducting research increases student engagement and retention in science. We describe case studies in five different educational settings in Canada and the USA: a programme for primary and secondary school students (ages 5-18), a year-long professional development programme for secondary school teachers, projects embedding this research into courses in a post-secondary 2-year institution and a degree-granting university, and a citizen science project. We argue that these projects are successful because the scientific content is authentic and compelling, DNA barcoding is conceptually and technically straightforward, the workflow is adaptable to a variety of situations, and online tools exist that allow participants to contribute high-quality data to the international research effort. Evidence of success includes the broad adoption of these programmes and assessment results demonstrating that participants are gaining both knowledge and confidence. There are exciting opportunities for coordination among educational projects in the future. © 2016 The Authors.

Rieger S.,MDI Biological Laboratory | Zhao H.,Chongqing Medical University | Martin P.,MDI Biological Laboratory | Abe K.,Tokai University | Lisse T.S.,MDI Biological Laboratory
Cell Biochemistry and Function | Year: 2015

The cutaneous wound repair process involves balancing a dynamic series of events ranging from inflammation, oxidative stress, cell migration, proliferation, survival and differentiation. A complex series of secreted trophic factors, cytokines, surface and intracellular proteins are expressed in a temporospatial manner to restore skin integrity after wounding. Impaired initiation, maintenance or termination of the tissue repair processes can lead to perturbed healing, necrosis, fibrosis or even cancer. Nuclear hormone receptors (NHRs) in the cutaneous environment regulate tissue repair processes such as fibroplasia and angiogenesis. Defects in functional NHRs and their ligands are associated with the clinical phenotypes of chronic non-healing wounds and skin endocrine disorders. The functional relationship between NHRs and skin niche cells such as epidermal keratinocytes and dermal fibroblasts is pivotal for successful wound closure and permanent repair. The aim of this review is to delineate the cutaneous effects and cross-talk of various nuclear receptors upon injury towards functional tissue restoration. © 2014 John Wiley & Sons, Ltd.

Losick V.P.,MDI Biological Laboratory | Jun A.S.,Wilmer Eye Institute | Spradling A.C.,MDI Biological Laboratory
PLoS ONE | Year: 2016

Tissue integrity and homeostasis often rely on the proliferation of stem cells or differentiated cells to replace lost, aged, or damaged cells. Recently, we described an alternative source of cell replacement- The expansion of resident, non-dividing diploid cells by wound-induced polyploidization (WIP). Here we show that the magnitude of WIP is proportional to the extent of cell loss using a new semi-automated assay with single cell resolution. Hippo and JNK signaling regulate WIP; unexpectedly however, JNK signaling through AP-1 limits rather than stimulates the level of Yki activation and polyploidization in the Drosophila epidermis. We found that polyploidization also quantitatively compensates for cell loss in a mammalian tissue, mouse corneal endothelium, where increased cell death occurs with age in a mouse model of Fuchs Endothelial Corneal Dystrophy (FECD). Our results suggest that WIP is an evolutionarily conserved homeostatic mechanism that maintains the size and synthetic capacity of adult tissues. ©2016 Losick et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Howard A.C.,MDI Biological Laboratory | Rollins J.,MDI Biological Laboratory | Snow S.,MDI Biological Laboratory | Castor S.,The Jackson Laboratory | Rogers A.N.,MDI Biological Laboratory
Aging Cell | Year: 2016

Although certain methods of lowering and/or altering mRNA translation are associated with increased lifespan, the mechanisms underlying this effect remain largely unknown. We previously showed that the increased lifespan conferred by reducing expression of eukaryotic translation initiation factor 4G (eIF4G/IFG-1) enhances survival under starvation conditions while shifting protein expression toward factors involved with maintaining ER-dependent protein and lipid balance. In this study, we investigated changes in ER homeostasis and found that lower eIF4G/IFG-1 increased survival under conditions of ER stress. Enhanced survival required the ER stress sensor gene ire-1 and the ER calcium ATPase gene sca-1 and corresponded with increased translation of chaperones that mediate the ER unfolded protein response (UPRER). Surprisingly, the heat-shock transcription factor gene hsf-1 was also required for enhanced survival, despite having little or no influence on the ability of wild-type animals to survive ER stress. The requirement for hsf-1 led us to re-evaluate the role of eIF4G/IFG-1 on thermotolerance. Results show that lowering expression of this translation factor enhanced thermotolerance, but only after prolonged attenuation, the timing of which corresponded to increased transcription of heat-shock factor transcriptional targets. Results indicate that restricting overall translation through eIF4G/IFG-1 enhances ER and cytoplasmic proteostasis through a mechanism that relies heavily on hsf-1. © 2016 The Anatomical Society and John Wiley & Sons Ltd.

Bodnar A.G.,Bermuda Institute of Ocean Sciences | Coffman J.A.,MDI Biological Laboratory
Aging Cell | Year: 2016

Aging in many animals is characterized by a failure to maintain tissue homeostasis and the loss of regenerative capacity. In this study, the ability to maintain tissue homeostasis and regenerative potential was investigated in sea urchins, a novel model to study longevity and negligible senescence. Sea urchins grow indeterminately, regenerate damaged appendages and reproduce throughout their lifespan and yet different species are reported to have very different life expectancies (ranging from 4 to more than 100 years). Quantitative analyses of cell proliferation and apoptosis indicated a low level of cell turnover in tissues of young and old sea urchins of species with different lifespans (Lytechinus variegatus, Strongylocentrotus purpuratus and Mesocentrotus franciscanus). The ability to regenerate damaged tissue was maintained with age as assessed by the regrowth of amputated spines and tube feet (motor and sensory appendages). Expression of genes involved in cell proliferation (pcna), telomere maintenance (tert) and multipotency (seawi and vasa) was maintained with age in somatic tissues. Immunolocalization of the Vasa protein to areas of the tube feet, spines, radial nerve, esophagus and a sub-population of circulating coelomocytes suggests the presence of multipotent cells that may play a role in normal tissue homeostasis and the regenerative potential of external appendages. The results indicate that regenerative potential was maintained with age regardless of lifespan, contrary to the expectation that shorter lived species would invest less in maintenance and repair. © 2016 The Anatomical Society and John Wiley & Sons Ltd.

Hartig E.I.,MDI Biological Laboratory | Zhu S.,MDI Biological Laboratory | King B.L.,MDI Biological Laboratory | Coffman J.A.,MDI Biological Laboratory
Biology Open | Year: 2016

Chronic early-life stress increases adult susceptibility to numerous health problems linked to chronic inflammation. One way that this may occur is via glucocorticoid-induced developmental programming. To gain insight into such programming we treated zebrafish embryos with cortisol and examined the effects on both larvae and adults. Treated larvae had elevated whole-body cortisol and glucocorticoid signaling, and upregulated genes associated with defense response and immune system processes. In adulthood the treated fish maintained elevated basal cortisol levels in the absence of exogenous cortisol, and constitutively mis-expressed genes involved in defense response and its regulation. Adults derived from cortisol-treated embryos displayed defective tailfin regeneration, heightened basal expression of proinflammatory genes, and failure to appropriately regulate those genes following injury or immunological challenge. These results support the hypothesis that chronically elevated glucocorticoid signaling early in life directs development of a pro-inflammatory adult phenotype, at the expense of immunoregulation and somatic regenerative capacity. © 2016. Published by The Company of Biologists Ltd.

Arenas-Mena C.,CUNY - College of Staten Island | Coffman J.A.,MDI Biological Laboratory
Developmental Dynamics | Year: 2015

It is proposed that the evolution of complex animals required repressive genetic mechanisms for controlling the transcriptional and proliferative potency of cells. Unicellular organisms are transcriptionally potent, able to express their full genetic complement as the need arises through their life cycle, whereas differentiated cells of multicellular organisms can only express a fraction of their genomic potential. Likewise, whereas cell proliferation in unicellular organisms is primarily limited by nutrient availability, cell proliferation in multicellular organisms is developmentally regulated. Repressive genetic controls limiting the potency of cells at the end of ontogeny would have stabilized the gene expression states of differentiated cells and prevented disruptive proliferation, allowing the emergence of diverse cell types and functional shapes. We propose that distal cis-regulatory elements represent the primary innovations that set the stage for the evolution of developmental gene regulatory networks and the repressive control of key multipotency and cell-cycle control genes. The testable prediction of this model is that the genomes of extant animals, unlike those of our unicellular relatives, encode gene regulatory circuits dedicated to the developmental control of transcriptional and proliferative potency. © 2015 Wiley Periodicals, Inc.

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