Childs lab, University of Calgary
Elucidating zebrafish angiogenesis:
We are taking a genetic approach to identify new genes involved in angiogenesis, the process by which new blood vessels develop. The cardiovascular system is critical for the survival of vertebrates, and is one of the earliest organ systems to develop in an embryo. Our experimental approach is to identify mutant animals with defects in cardiovascular development during embryogenesis, and then to clone the gene underlying each defect. We then examine the role of these genes in embryonic development and disease. Angiogenesis is altered in many diseases; for instance, it is increased during tumor growth and in diabetic retinopathy. In other cases, impaired angiogenesis can also lead to disease, for instance, in ischemia. The understanding of genes controlling blood vessel growth may therefore lead to new treatments for disease.
Zebrafish as a model system:
Zebrafish are a common tropical fish that develop as transparent, externally fertilized embryos. We can observe their development during all stages of embryogenesis under a microscope, in contrast to mammals which develop in utero and are inaccessible. We use zebrafish as a model system because they are small, transparent, and their cardiovascular system develops very similarly to that of mammals. This allows us to do very detailed screens for subtle genetic defects. Each pair of zebrafish lays a large number of eggs each week. This greatly facilitates genetic analysis. Furthermore, as the zebrafish genome is sequenced, it is clear that essentially all of the known genes involved in the establishment of the early vascular system are conserved between fish and mammals.
• Vascular patterning
• Vascular specification
• Origins of vascular
and visceral smooth muscle in zebrafish
• Genetic pathways
leading to vascular stabilization
1. Whitesell, T.R., Kennedy, R.M., Carter, A.D., Rollins, E.L., Georgijevic, S., Santoro, M.M. & Childs, S.J. An alpha-Smooth Muscle Actin (acta2/alphasma) Zebrafish Transgenic Line Marking Vascular Mural Cells and Visceral Smooth Muscle Cells. PLoS One 9, e90590 (2014).
2. Tamplin, O.J., Durand, E.M., Carr, L.A., Childs, S.J., Li, P., Yzaguirre, A.D., Speck, N.A. & Zon, L.I. Live imaging of hematopoietic stem cell lodgement reveals dynamic endothelial niche remodeling. Cell Accepted, In Press (2014).
3. Sarsons, C.D., Yaehne, K., Tekrony, A., Childs, S.J., Rinker, K.D. & Cramb, D. Testing nanoparticles for angiogenesis-related disease: Charting the fastest route to the clinic. Journal of Biomedical Nanotechnology 10, 1641-1676 (2014).
4. French, C.R., Seshadri, S., Destefano, A.L., Fornage, M., Arnold, C.R., Gage, P.J., Skarie, J.M., Dobyns, W.B., Millen, K.J., Liu, T., Dietz, W., Kume, T., Hofker, M., Emery, D.J., Childs, S.J., Waskiewicz, A.J. & Lehmann, O.J. Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. J Clin Investigation 124, 4877-4881 (2014).
5. Ebert, A.M., Childs, S.J., Hehr, C.L., Cechmanek, P.B. & McFarlane, S. Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion. Development 141, 2473-2482 (2014).
6. Yaehne, K., Tekrony, A., Clancy, A., Gregoriou, Y., Walker, J., Dean, K., Nguyen, T., Doiron, A., Rinker, K., Jiang, X.Y., Childs, S. & Cramb, D. Nanoparticle accumulation in angiogenic tissues: towards predictable pharmacokinetics. Small 9, 3118-3127 (2013).
7. Zeng, L. & Childs, S.J. The smooth muscle microRNA miR-145 regulates gut epithelial development via a paracrine mechanism. Developmental Biology 367, 178-186 (2012).
8. Liu, J., Zeng, L., Kennedy, R.M., Gruenig, N.M. & Childs, S.J. betaPix plays a dual role in cerebral vascular stability and angiogenesis, and interacts with integrin alpha(v)beta(8). Developmental Biology 363, 95-105 (2012).
9. Ebert, A.M., Lamont, R.E., Childs, S.J. & McFarlane, S. Neuronal expression of class 6 semaphorins in zebrafish. Gene Expr Patterns 12, 6 (2012).
10. Chik, J.K., Schriemer, D.C., Childs, S.J. & McGhee, J.D. Proteome of the Caenorhabditis elegans oocyte. J Proteome Res 10, 2300-2305 (2011).
11. Zuccolo, J., Bau, J., Childs, S.J., Goss, G.G., Sensen, C.W. & Deans, J.P. Phylogenetic analysis of the MS4A and TMEM176 gene families. PLoS One 5, e9369 (2010).
12. Mably, J.D. & Childs, S.J. Developmental Physiology of the Zebrafish Cardiovascular System, in Fish Physiology:Zebrafish, Vol. 29. (eds. S.F. Perry, M. Ekker, A.P. Farrell & C.J. Brauner) 249-287 (Academic Press, 2010).
13. Lamont, R.E., Vu, W., Carter, A.D., Serluca, F.C., MacRae, C.A. & Childs, S.J. Hedgehog signaling via angiopoietin1 is required for developmental vascular stability. Mech Dev 127, 159-168 (2010).
14. Christie, T.L., Carter, A., Rollins, E.L. & Childs, S.J. Syk and Zap-70 function redundantly to promote angioblast migration. Dev Biol 340, 22-29 (2010).
15. Zeng, L., Carter, A.D. & Childs, S.J. miR-145 directs intestinal maturation in zebrafish. Proc Natl Acad Sci U S A 106, 17793-17798 (2009).
16. Lamont, R.E., Lamont, E.J. & Childs, S.J. Antagonistic interactions among Plexins regulate the timing of intersegmental vessel formation. Dev Biol 331, 199-209 (2009).
Biochemistry and Molecular Biology
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