Congress Abstracts - Society for Developmental Biology

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-
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