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Small molecule screen for compounds that affect vascular development in the zebrafish retina
Södertörn University, School of Life Sciences. Karolinska Institutet / Harvard Medical School/MEEI, Boston, USA.
Harvard Medical School/MEEI, Boston, USA.
Massachusetts General Hospital, USA.
Harvard Medical School/MEEI, Boston, USA.
2009 (English)In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, no 5-6, 464-477 p.Article in journal (Refereed) Published
Abstract [en]

Blood vessel formation in the vertebrate eye is a precisely regulated process. in the human retina, both an excess and a deficiency of blood vessels may lead to a loss of vision. To gain insight into the molecular basis of vessel formation in the vertebrate retina and to develop pharmacological means of manipulating this process in a living organism, we further characterized the embryonic zebrafish eye vasculature, and performed a small molecule screen for compounds that affect blood vessel morphogenesis. The screening of approximately 2000 compounds revealed four small molecules that at specific concentrations affect retinal vessel morphology but do not produce obvious changes in trunk vessels, or in the neuronal architecture of the retina. Of these, two induce a pronounced widening of vessel diameter without a substantial loss of vessel number, one compound produces a loss of retinal blood vessels accompanied by a mild increase of their diameter, and finally one other generates a severe loss of retinal vessels. This work demonstrates the utility of zebrafish as a screening tool for small molecules that affect eye vasculature and presents several compounds of potential therapeutic importance.

Place, publisher, year, edition, pages
2009. Vol. 126, no 5-6, 464-477 p.
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:sh:diva-13901DOI: 10.1016/j.mod.2009.01.002ISI: 000266975100016PubMedID: 19445054ScopusID: 2-s2.0-67349147007OAI: oai:DiVA.org:sh-13901DiVA: diva2:465038
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2016-12-29Bibliographically approved
In thesis
1. Teleost retina: a model for study neurogenesis and angiogenesis
Open this publication in new window or tab >>Teleost retina: a model for study neurogenesis and angiogenesis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Teleost models, zebrafish and medaka have become popular models to study various aspects of developmental biology and genetics. The rapid embryonic development, transparent embryos and the availability of many mutants for various developmental and molecular pathways contribute to the usefulness of these models. The availability of various biochemical, molecular and genetic techniques applicable on these models facilitate in dissecting developmental processes. Teleost retina shows very high similarity to that seen in mammalian retina. The arrangement of the six types of neurons and one type of glia is very similar. Zebrafish has been extensively used in gaining insight into the development and functioning of the retina. Medaka, on the other hand has not been so extensively capitalized as zebrafish. The current study characterizes expression of genes mainly from the nuclear receptor family and establishes the role of zebrafish liver x receptor in governing the size, patterning and neurogenesis of the retina in zebrafish. We also establish the time line of the retinal patterning of medaka retina. Zebrafish and medaka retina show both similarity and difference in the developmental events governing the patterning of the retina. In zebrafish, retinal neurogenesis follows a fan gradient pattern starting at the ventro-nasal region. In medaka, neurogenesis starts from the central retina. An additional, second domain of neurogenesis is seen with the patterning of photoreceptors in medaka. This observation highlights the possibility of utilizing these two species as comparative models in gaining rapid understanding of retinal development and function. This study also establishes the time line of vascular development in the zebrafish retina, an important event required for normal function. Similar to neurogenesis, vasculaturedevelops rapidly and this feature was utilized to develop a small molecule-screening assay. The screening resulted in identification of five compounds that produced phenotype ranging from decrease in the number of vessels to loss of vessels specifically in the retina. To gain insight into the mode of action, further analyses of three of the five identified compounds, using either morpholino knockdown or structural similarity search was done. This study highlights the advantage of using zebrafish model to perform medically relevant chemical screen.

Place, publisher, year, edition, pages
Stockholm: Karolinska instiutet, 2009. 37 p.
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-31551 (URN)978-91-7409-365-0 (ISBN)
Public defence
2009-03-30, Månen, Alfred Nobels allé 8, Huddinge, 09:00
Opponent
Supervisors
Available from: 2016-12-29 Created: 2016-12-29 Last updated: 2016-12-29Bibliographically approved

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