Molecular Genetics of Organ Morphogenesis
One of my laboratory's major goals is to understand how individual cells control their shapes and coordinate with other cells to create the complex organs found in multicellular organisms. To this end, we are using genetic, molecular and cell biological approaches to identify and study genes required for the morphogenesis of the Drosophila tracheal system. The Drosophila tracheal system is a ramifying network of epithelial tubes that serves as a combined airway and vascular system for delivering oxygen to tissues in the fly. At the molecular level, Drosophila tracheal development has striking similarities to both vertebrate lung and vascular development. These similarities, coupled with the simplicity of the tracheal system and the power of Drosophila genetics, makes the tracheal system an outstanding model system for understanding the morphogenesis of the tubular epithelia that are central to such vertebrate organs as the vascular system, lung and kidney.
We have shown that the size of the Drosophila tracheal tubes is controlled by genetic programs and have identified mutations in more than fifteen genes that cause the tracheal tubes to have abnormal lengths or diameters. We, and others, have cloned many of these genes and shown that many of them encode components of a cell-cell junction that also control paracellular diffusion, cell polarity and cell growth. We are characterizing the cell biological and biochemical functions of these proteins in both flies and vertebrates, and are working to clone additional genes that control cell shape.
A second major goal of my lab is to understand how CO2 levels are sensed by non-neuronal cells and how subsequent signal transduction and effector pathways alter organismal physiology in response to elevated CO2. In particular, in collaboration with the laboratory of Dr. Peter Sporn at Northwestern’s medical school, we are investigating how elevated CO2 suppresses innate immune responses in flies and mammals. My lab has developed Drosophila as a genetically tractable model of hypercapnic immune suppression, and shown that there are many parallels between innate immune suppression by hypercapnia in flies and mammals. To identify genes that mediate the effects of CO2 on the immune system, we performed a genome-wide RNAi screen using Drosophila S2* cells (Helenius et al., submitted) and are now characterizing hits from the screen. The first hit we have a characterized is Zfh2, which encodes a large transcription factor. We have shown that tissue-specific knockdown of zfh2 in the fat body (the major immune organ in the fly) can protect flies from increased mortality of S. aureus infection that normally results from exposing the flies to elevated CO2 before infection. Dr. Sporn’s lab is currently testing whether the mammalian orthologs of Zfh2, ZFHX3/ATBF1 and ZFHX4 mediate hypercapnic immune suppression in mouse and human tissue culture cells.
Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression. Helenius IT, Nair A, Trejo Bittar HE, Sznajder JI, Sporn PHS, and Beitel GJ. Journal of Biomolecular Screening. 2016 April;21(4):363-371.
Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen. Helenius IT, Haake RJ, Kwon Y-J, Hu JA, Krupinski T, Casalino-Matsuda SM, Sporn PHS, Sznajder JI, and Beitel GJ. Journal of Immunology. 2016 January 15;196(2):655-667.
Three-ring circus without a ringmaster: Self-organization of supracellular actin ring patterns during epithelial morphogenesis. Gov NS, McSharry SS, and Beitel GJ. PNAS. 2015 July 14;112(28):8521-8522.
Hypercapnia Inhibits Autophagy and Bacterial Killing in Human Macrophages by Increasing Expression of Bcl-2 and Bcl-xL. Casalino-Matsuda SM, Nair A, Beitel GJ, Gates KL, and Sporn PHS. Journal of Immunology. 2015 June 1;194(11):5388-5396.
Non-Canonical Roles for Yorkie and Drosophila Inhibitor of Apoptosis 1 in Epithelial Tube Size Control. Robbins RM, Gbur SC, and Beitel GJ. PLoS ONE. 2014 July 18;9(7):e101609.
Tubulogenesis. Iruela-Arispe ML and Beitel GJ. Development. 2013 July 15;140(14):2851-2855.
Evolutionary Conserved Role of c-Jun-N-Terminal Kinase in CO2-Induced Epithelial Dysfunction. Vadász I, Dada LA, Briva A, Helenius IT, Sharabi K, Welch LC, Kelly AM, Grzesik BA, Budinger GRS, Liu J, Seeger W, Beitel GJ, Gruenbaum Y, and Sznajder JI. PLoS ONE. 2012 October 8;7(10):e46696.
Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size. Nelson KS, Khan Z, Molnár I, Mihály J, Kaschube M, and Beitel GJ. Nature Cell Biology. 2012 May;14(5):518-525.
The single Drosophila ZO-1 protein Polychaetoid regulates embryonic morphogenesis in coordination with Canoe/afadin and Enabled. Choi W, Jung K-C, Nelson KS, Bhat MA, Beitel GJ, Peifer M, and Fanning AS. Molecular Biology of the Cell. 2011 June 15;22(12):2010-2030.
Vascular Lumen Formation: Negativity Will Tear Us Apart. Robbins RM and Beitel GJ. Current Biology. 2010 November 23;20(22):R973-R975.
Echinoid regulates tracheal morphology and fusion cell fate in Drosophila. Laplante C, Paul SM, Beitel GJ, and Nilson LA. Developmental Dynamics. 2010 September;239(9):2509-2519.
View all publications by Greg J. Beitel listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.