Michel Bagnat, Ph.D. (EMBL, Heidelberg)
Assistant Professor, Cell Biology
333B Nanaline Duke Bldg., Box 3709,
Duke University Medical Center,
Durham, NC 27710
Our laboratory is interested in studying how basic cellular processes define the shape and size of complex multicellular structures such as organs. Our major focus is to study how biological tubes are assembled and to understand the role hydrostatic pressure plays as a developmental force. Fluid movement into enclosed lumenal or intracellular spaces creates hydrostatic pressure that can serve as a driving force for organogenesis and long range morphogenetic events such as axis elongation. Using zebrafish we investigate:
Notochord and Spine Formation
The zebrafish notochord is comprised of large fluid-filled vacuoles. The notochord acts as a hydrostatic skeleton for the embryo early in development and works to elongate the embryo along the anterior-posterior axis. Later during development the notochord provides a rigid framework for bone deposition during spine formation. We have shown that when notochord vacuoles are disrupted, the embryos are shorter and the spine develops kinks, similar to those seen in scoliosis patients. Using zebrafish we are studying the cellular and molecular mechanisms controlling notochord vacuole biogenesis and how the notochord acts a hydrostatic scaffold during spine formation. These studies provide a framework for the understanding of the developmental roles of the vertebrate notochord and the etiology of scoliosis.
Single lumen formation and lumen expansion
Although tubes develop in a variety of ways, a defining characteristic of a tube is the presence of a single central lumen. We use the zebrafish gut as a model to investigate the process of lumen formation. We have previously shown that fluid accumulation is required for the enlargement and coalescence of multiple small lumens. Fluid secretion is typically driven by modulating osmotic gradients, regulated by the movement of anions. Paracellular ion transport drives fluid accumulation during lumen coalescence and expansion in the gut. In other contexts, fluid secretion is regulated by chloride transport mediated by the CFTR channel. In zebrafish, Cftr regulates fluid secretion and lumen expansion necessary for the function of Kupffer's vesicle, a transient fluid-filled organ. Currently, we are investigating additional mechanisms that regulate cellular rearrangements during the process of single lumen formation.
Apical membrane biogenesis
The biogenesis of the apical surface is of particular interest in lumen formation of organs during development and defects in apical protein sorting have been linked to the etiology of numerous diseases. We are interested in determining how biogenesis of the apical surface occurs by following a comprehensive approach combining forward genetics in zebrafish and cell biological methods to elucidate genes involved in apical membrane biogenesis and lumen formation.
Ryan S, Willer J, Marjoram L, Bagwell J, Mankiewicz J, Leshchiner I, Goessling W, Bagnat M, and Katsanis N. (2013) Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish. Development. 140:4445-4451.
Ellis K, Hoffman BD, Bagnat M. (2013) The vacuole within: How cellular organization dictates notochord function. Bioarchitecture. 26;3(3).
Ellis K., Bagwell J., Bagnat M. (2013). Notochord vacuoles are lysosome-related organelles that function in axis and spine morphogenesis. J. Cell Biol. 200(5):667-679.
**This article is featured in: In Focus: Notochord vacuoles make a rod for the vertebrate back. J Cell Biol. 200(5):553- and: SCIENCENOW: and: Science in the Clouds
Navis, A., Marjoram, L. and Bagnat, M. (2013) cftr controls lumen expansion and function of Kupffer’s vesicle in zebrafish. Development 140(8):1703-12.
Bagnat M., Navis A., Herbstreith S., Brand-Arzamendi K., Curado S., Gabriel S., Mostov K., Huisken J., Stainier D.Y. (2010) Cse1l is a negative regulator of CFTR-dependent fluid secretion. Curr. Bio. 20:1840-5.
Bagnat M., Cheung I.D, Mostov K.E., and Stainier D.Y. (2007) Genetic control of single lumen formation in the zebrafish gut. Nat Cell Biol. 9:954-60.