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Frank  Costantini
Frank Costantini
Professor, Genetics and Development


Address: 701 West 168th Street Room 1418 New York NY 10472
Phone: 212-305-6814
Fax: 212-923-2090
E-mail:

fdc3@columbia.edu

Education and Training:
Ph.D. 1980, California Institute of Technology
Postdoctoral Fellowship 1980-82, Oxford University
Affiliations:
bullet  Department of Genetics and Development
bullet  Herbert Irving Comprehensive Cancer Center
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Training Activities:
bullet  Graduate Program in Genetics and Development
bullet  MD/PhD Program
bullet  Integrated Program in Cellular, Molecular and Biophysicial Studies
Research Summary:
(800 words, max)
Genetics of kidney development in the mouse; cellular and genetic basis of epithelial branching morphogenesis
Current Research:
The general interest of our laboratory is in the role of cell-cell signaling and signal transduction in renal organogenesis, with emphasis on the Ret receptor tyrosine kinase. Since discovering that Ret is required for kidney development, we have focused on understanding the role of Ret, its ligand GDNF, and downstream signaling pathways and target genes in branching morphogenesis. Our main approach is to generate transgenic, chimeric, knock-in and knock-out mice, to manipulate the expression and/or sequence of proteins in the GDNF/Ret signaling pathway, and then to investigate the effects of these manipulations during development in vivo and in organ explant cultures. Some of the questions currently addressed are:

· What changes in the behavior of ureteric bud cells are induced by GDNF/Ret signaling, and how do these events contribute to branching morphogenesis?

· Do the expression patterns of GDNF and Ret provide positional information that determines the specific pattern of ureteric bud branching?

· What intracellular signaling pathways triggered by GDNF/Ret are important for ureteric bud development, and what target genes are activated or repressed by GDNF/Ret signaling?

· What are the developmental functions of these target genes, and how do they mediate the effects of GDNF?

· How does GDNF/Ret signaling interact with other signaling pathways (e.g., those activated by FGFs, Wnts, and BMPs) to regulate ureteric bud growth and branching?

· What are the properties of stem cells for the ureteric bud and nephron lineages in the developing kidney.

Studies of renal branching morphogenesis have been greatly aided by an organ culture system in which the early events of kidney development can be visualized in real time, and we have generated several strains of mice and embryonic stem cell lines that facilitate such studies. We continue to develop new reporter strains of mice that will be useful for visualizing dynamic processes such as cell migration, changes in cell shape and cell division in developing kidneys.

Publications:
(6 max)
1. Cebrian, C., Asai, N., D’Agati, V. and Costantini, F.: (2014) The number of fetal nephron progenitor cells limits ureteric branching and adult nephron endowment.  Cell Reports  7: 127–137.

2. Packard, A, Georgas, K, Michos, O, Riccio, P, Cebrian, C, Combes, AN, Ju, A, Ferrer-Vaquer, A, Hadjantonakis, A-K, Zong, H, Little, MH, Costantini, F. : (2013) Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud.  Developmental Cell  27(3): 319-330.

3. Costantini, F. and Kopan, R. : (2010) Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development.  Developmental Cell   18(5): 698-712.

4. Michos, O., Cebrian, C., Hyink D., Grieshammer U., Williams, L., D’Agati, V., Licht, J.D., Martin, G.R. and Costantini, F.: (2010) Kidney development in the absence of Gdnf and Spry1 requires Fgf10.  PLos Genetics   6(1):e1000809: 

5. Lu, B.C., Cebrian, C, Chi, X., Kuure, S., Kuo, R., Bates, C.M., Arber, S., Hassell, J., MacNeil, L., Hoshi, M., Jain, S., Asai, N., Takahashi, M., Schmidt-Ott, K., Barasch, J., D’Agati, V., and Costantini, F.: (2009) Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis.  Nature Genetics   41: 1295-1302.

6. Chi, X, O Michos, R Shakya, P Riccio, H Enomoto, JD Licht, N Asai, M Takahashi, N Ohgami, M Kato, C Mendelsohn and F Costantini.: (2009) Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis.  Developmental Cell  17(2): 199-209.

URL for lab page:
 

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