Congress Abstracts - Society for Developmental Biology

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Program/Abstract # 547 Control of daughter cell proliferation in the embryonic CNS by Temporal, Hox and Notch cues Bivik, Caroline; Baumgardt, Magnus; Karlsson, Daniel; Yaghmaeian, Behzad; MacDonald, Ryan; Gunnar, Erika; Thor, Stefan (Linkoping Univ, Sweden) Substantial progress has been made with respect to cell fate specification in the nervous system. In contrast, less is known regarding the control of proliferation, such that proper numbers of each neural cell type is generated. In the embryonic Drosophila nerve cord, neuroblasts (NBs) generate the CNS by dividing asymmetrically, renewing themselves while budding off daughter cells, the ganglion mother cells (GMC). Each GMC in turn divides asymmetrically to produce two different neurons and/or glia. This is denoted a Type I division mode, because daughters divide once. Recent studies have identified an alternate division mode, where NBs bud off daughters that directly differentiate. We propose that this division mode should be denoted Type 0, since daughter cells do not divide. However, the extent of Type I and Type 0 proliferation in the CNS, and the extent to which NBs display switches in the proliferation modes were hitherto unknown. By mapping several specific NB lineages, and conducting a global analysis of division mode, we find that some half of all NB lineages in the nerve cord undergo a Type I to Type 0 switch. While Prospero plays a key role in controlling daughter cell proliferation in Type I, Pros does not direct Type 0 mode. The switch from Type I to Type 0 is combinatorially controlled by the temporal genes castor and grainyhead, the Hox gene Antennapedia and the Notch pathway. These regulatory cues are activated in the latter part of many lineages, thus ensuring proper temporal control. Analysis of 22 key cell cycle genes showed that the dacapo gene (p21CIP/p27KIP) is the key player triggering this switch. These findings reveal a novel global principle for proliferation control in the Drosophila CNS. Program/Abstract # 548 Regulation of neural stem cell transition from symmetric to asymmetric cell division Contreras Sepúlveda, Esteban; Brand, Andrea (Cambridge, UK) Neural stem cells (NSCs) have the ability to divide symmetrically to amplify their pool and asymmetrically to self-renew and differentiate into neurons or glial cells. Precise control of NSC proliferation is essential for the proper development of the nervous system. Disrupting the balance between symmetric and asymmetric division can cause NSC overproliferation, triggering tumour formation, or premature differentiation, resulting in fewer neurons or glial cells. To understand how NSCs control the balance between amplification and differentiation we use the developing visual system of Drosophila melanogaster, the optic lobe, as a model. Neurogenesis in the optic lobe resembles the development of mammalian cerebral cortex. The optic lobe is composed of two types of NSCs: symmetrically dividing neuroepithelial (NE) cells and asymmetrically dividing neuroblasts (NBs). NE cells transform into NBs to generate optic lobe neurons in a similar manner than NE cells and radial glia in the cerebral cortex. Several signalling pathways (JAK/STAT, Notch, EGFR) have been described to regulate the transition from symmetric to asymmetric division, however, interactions between these pathways remain unclear suggesting that further regulatory components may be involved. To identify new genes controlling the switch from symmetric to asymmetric division, we took advantage of a transcriptome analysis of NE cells and NBs previously performed in the lab. We knocked down 35 genes by transgenic RNAi. Eight of these genes showed a phenotype, including two defects in adult optic lobe morphology and one impairment in NE cell to NB transformation, suggesting a role in the transition from symmetric to asymmetric cell division. Program/Abstract # 549 Kif11 dependent cell cycle progression in radial glial cells is required for proper neurogenesis in the zebrafish neural tube. Johnson, Kimberly A. (U Mass Amherst, USA); Moriarty, Chelsea; Tania, Nessy; Ortman, Alissa; DiPietrantonio, Kristina; Edens, Brittany; Eisenman, Jean; Ok Deborah; Krikorian, Sarah; Gole, Christophe; Barresi, Michael (Smith College, USA) Radial glia serve as the resident neural stem cells in the embryonic vertebrate nervous system, and their proliferation must be tightly regulated to generate the correct number of neuronal and glial cell progeny in the neural tube. We recently identified the kif11 zebrafish mutant during a forward genetic screen that displayed a significant increase in radial glial cell bodies at the ventricular zone throughout the developing spinal cord. Kif11, also known as Eg5, is a plus-end directed motor protein responsible for stabilizing and separating the bipolar mitotic spindle. We show here that Gfap+ radial glia express kif11 throughout the ventricular zone and floor plate. Loss of Kif11 by mutation or pharmacological inhibition with S-trityl-L-cysteine (STLC) results in monoastral spindle formation in radial glial cells characteristic of mitotic arrest and accumulation of M-phase radial glia over time at the ventricular zone. Mathematical modeling of the radial glial accumulation predicted a delayed entry into the cell cycle and increased cell death in kif11 mutants, which was supported by BrdU pulse-fix analysis and anti-activated Caspase 3 labeling, respectively. Lastly, we show that secondary interneurons, motorneurons, and oligodendroglia were significantly reduced following the loss of Kif11 function. We propose a model that Kif11 functions during mitotic spindle formation to facilitate the progression of radial glia through mitosis, which leads to the maturation of progeny into specific secondary neuronal and glial lineages in the developing neural tube. Currently we are testing this model with a genetic cell ablation line to determine whether radial glia are required for the formation of these cell lineages. Program/Abstract 550 Withdrawn 158
Program/Abstract # 551 Evolutionarily Repurposed Networks Reveal the Well-Known Antifungal Drug Thiabendazole to Be a Novel Vascular Disrupting Agent and It Acts Through Microtubule-associated Proteins Cha, Hye Ji; Byrom, Michelle (UT-Austin, USA); Mead, Paul (St Jude Chidren’s Res Hosp, USA); Ellington, Andrew; Wallingford, John; Marcotte, Edward (UT- Austin, USA) In the course of systematically identifying associations between genes and traits, we found gene modules that were shared between evolutionary distant organisms. In particular, genes responding to stress in yeast, which have no blood vessels, regulate angiogenesis in vertebrates. By analyzing such repurposed networks, we reasoned that small molecule inhibitors targeting the pathway in yeast might act as angiogenesis inhibitors suitable for chemotherapy in vertebrates. We computationally prioritized candidates based upon measured synthetic genetic interaction of known drugs. This strategy led to the finding that thiabendazole (TBZ), an orally available FDA-approved antifungal drug, also potently inhibits angiogenesis in animal models and in human cells. Moreover, TBZ disassembles pre-existing vessels, marking it as a Vascular Disrupting Agent and thus as a potential complementary therapeutic for use in combination with current anti-angiogenic therapies. In vivo imaging and a quantitative in vitro assay suggest that defects in vascular morphogenesis may stem from impairment of junctional integrity and endothelial cell behavior. Cellular phenotypes implied increased Rho signaling, and indeed, pharmacological disruption of Rho kinase elicited rescue of the TBZ-induced motility defect. TBZ had a very slight effect on the organization of the microtubule, but significantly reduced the abundance of tubulin and impaired microtubuleassociated proteins. We also show that TBZ slows tumor growth and decreases vascular density in fibrosarcoma xenografts. Thus, an exploration of the evolutionary repurposed networks identified a potential new angiogenesis drug, and the organismal and cellular level analysis revealed its mode of action. Program/Abstract # 552 Hyperexcitability and exaggerated activation of hypoglossal motorneurons in 22q11DS neonatal mice Wang, Xin; Popratiloff, Anastas; Maynard, Thomas; Moody, Sally; LaMantia, Anthony; Mendelowitz, David Mendelowit (George Washington U, USA) Approximately 80% of infants with developmental disorders, including DiGeorge/22q11Delection Syndrome (22q11DS), possess feeding/swallowing disorders that compromise nutritional status, impede mental and physical development and increased risk of respiratory infection due to aspiration. Feeding is composed of a complex series of oro-facial events including the tongue moving food from the mouth to the oro-pharynx cavity. Normal feeding and swallowing depends upon an initial sequential activation of hypoglossal motor neurons (XII MNs) that innervate the tongue, followed by inhibition to ensure appropriately timed, uni-directional swallowing. In this study we tested if activation of XII MNs in the brainstem upon electrical stimulation of afferent fibers to initiate fictive swallowing is altered in neonatal 22q11DS (Lgdel) mice. Electrical stimulation of afferent fibers in wild-type control animals evoked an excitatory post-synaptic current (EPSC) in XII MNs that was sufficient to increase the firing activity in these neurons, that was followed by an inhibition of firing. In contrast, in LgDel pups, activation of the swallowing reflex elicited a larger than normal EPSC in XII MNs, and a prolonged and exaggerated increase in firing in XII MNs, that was followed by a sustained increase in firing in XII MNs devoid of a post-stimulus inhibition. These preliminary results suggest activation of the swallowing reflex causes an exaggerated hyperexcitability that is not followed by a normal inhibitory phase in XII MNs from LgDel pups. This hyperexcitability may be a potential cause of the swallowing dysfunction that can occur in children and infants with 22q11DS. Program/Abstract # 553 Modeling and computation of tissue growth driven by stem cell niches Figueroa, Seth Amin; Ovadia, Jeremy; Nie, Qing (UC-Irvine, USA) Formation and sustenance of a stem cell niche in stratified epithelia is key in controlling the tissue’s growth, morphology and regenerative capabilities. Often, stratified epithelia develop advantageous finger-like structures, such as rete ridges (or rete pegs) in the epidermis and the palisades of Vogt in the limbal corneal epithelium, along which the stem cell niche forms. These structures provide the basal layer of the epithelia with better protection and allow the tissue a more efficient wound response. However, how these undulating structures are formed, and the role of the spatial aspects of the niche on its local environment, is not yet fully understood. Interesting questions that arise from this are: (i) How do extracellular cues and the tissue’s underlying genetic system affect niche formation and tissue morphology? (ii) How does the tissue’s morphology, in return, affect the dynamics of the cell lineage and the stem cell system’s regenerative capabilities? Here we present a two dimensional multiscale model of stratified epithelial growth. The tissue growth model consists of stem cells, cell lineages and regulatory diffusive molecules. We have shown that stem cell niche development triggers distorted epithelial morphologies, similar to rete ridges, with stem cells accumulating along the tips, agreeing with experimental observations. Furthermore, we explore factors affecting niche formation and size, as well as potential biochemical regulations that can prompt formation and stabilization of an advantageous tissue architecture. Program/Abstract # 554 A new landmark-independent tool for assessing and quantifying morphologic change and phenotypic variation. Rolfe, Sara; Cox, Liza; Camci, Esra; Fu, Tina; Shapiro, Linda (U Washington, USA) Embryologic and developmental biology studies have traditionally relied on subjective assessments of gross phenotypic changes, whether for description of normal changes during embryogenesis or how mutants differ from controls. However, as advances in multi- 159
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International Society of Developmen
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neural crest cells (hNCC)) human em
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activity may determine the orientat
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Developmental cell signaling pathwa
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opposed roles during early gastrula
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functions by the recruitment of add
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function validated with explant stu
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Program/Abstract # 48 Modeling regu
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surface of the embryo. In zebrafish
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morphologies. Our analyses not only
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junctional proteins (RPE patterning
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Program/Abstract # 78 In vivo recep
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Program/Abstract # 85 Guts and gast
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Program/Abstract # 92 The C. elegan
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Program/Abstract # 98 A gradient of
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Program/Abstract # 106 Developing a
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NSCs, but not in neurons, bind not
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abnormalities in the development of
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Tbx4 and contributes to Tbx4 repres
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downregulated by polycomb-group pro
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Zac1 expression in the developing c
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understanding the mechanisms that u
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Program/Abstract # 156 Systematic I
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Program/Abstract # 163 Size regulat
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TACC3 was localized around the DNA
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Penaeid shrimp represent an importa
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tubule. Using live imaging of cultu
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show that cell polarity is disrupte
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process. However, a clear mechanist
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Zhang, Haoran; Wong, Elaine Yee-man
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condition. Kanyon embryos have a mi
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Program/Abstract # 218 Lfng regulat
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works in concert with basal cues fr
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medaka genome. These miRs are encod
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facilitan cambio en patrón morfoge
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coordinately regulate the expressio
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downstream asymmetric signals. The
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viability and morphology of over 20
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owser. The genomic differences obse
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evolutionary analysis to study the
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teleostei. Our data evidenced that
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ontogeny. The typical condition for
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examples whose Shh expression requi
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insights into the ancestral role of
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Program/Abstract # 308 Mechanistic
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Patients with Joubert Syndrome and
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Program/Abstract # 323 Drosophila g
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signalling during gut and enteric n
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normally form, hence producing prox
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survival in Shh mutant embryos foll
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conserved in amniotes other than ch
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maturation and function. We strive
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Urness, Lisa D; Bleyl, Steven B (Un
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Page 133 and 134: Program/Abstract # 462 Retinaldehyd
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Congress Abstracts - Society for Developmental Biology

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