Benjamin Fogelgren

Research in the Fogelgren lab investigates how regulation of intracellular protein transport affects cell differentiation and physiology.

1) Intracellular Trafficking Dynamics

We are interested in the dynamic regulation of the exocyst, an 8-protein complex that shuttles intracellular transport vesicles for polarized exocytosis. Highly conserved among eukaryotes, the exocyst acts as an effector for a handful of specific Rab GTPases that bind to subpopulations of transport vesicles. The association of exocyst subunits with specific vesicles, and the assembly of the exocyst holocomplex at specific subcellular locales for exocytosis, is tightly regulated by a series of small GTPases and kinases. GTPases are themselves regulated by a larger network of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which often are spatially restricted to specific areas of the cell and regulated by various cell signaling pathways. The exocyst is expressed by many mammalian cell types for a diverse array of directed exocytosis requirements. We use a variety of cell and animal models to better understanding the mechanics by which exocyst trafficking is regulated in different cell types, and how this contributes to cell differentiation and physiology.

2) Polarized Exocytosis in Renal Physiology

Critical for proper nephron physiology is the polarized exocytosis of transporters and receptors to either the apical (luminal) surface, or the basolateral surface. This polarized exocytosis is dynamically regulated by hormones, mechanical forces, and other signaling pathways. We study how this directed transport is controlled in different segments of the nephron, what role the exocyst plays, and how these processes are affected by renal pathologies such as chronic kidney disease (CKD). For these investigations, we used the Cre-lox transgenic system to generate the first conditional knockout mouse model for the exocyst by targeting the central subunit Sec10 (also called EXOC5). A global knockout of exocyst genes has proven lethal in mammals, and this conditional knockout approach allows targeted inactivation of the exocyst in a tissue-specific, and time-specific, manner. We also use a variety of renal epithelial cell models, which can be cultured on permeable supports in order to study apical vs. basal transport and cellular mechanics.

3) Urinary Tract Development and Disease

We have several research projects investigating genetic regulation of kidney and lower urinary tract embryonic development, and the congenital malformations that can arise. This includes a project on congenital obstructive nephropathy due to ureteropelvic junction obstruction (UPJO), which is the leading cause of kidney disease in infants and children. However, even relatively mild defects in urinary tract development can increase risk of adult diseases later in life. For example, infants born with low nephron endowment (small kidneys) are at higher risk of hypertension and cardiovascular disease as adults. We have several unique mouse models of congenital urinary tract malformations, which we use to investigate the etiology of these diseases, with the goal of better understanding the equivalent human diseases for improved therapeutic and prevention strategies.

4) Primary Cilia Assembly and Signaling

We have shown in several tissues that the exocyst contributes to the polarized exocytosis of proteins and membrane to the primary cilium. This organelle is found on many mammalian cell types and only numbers one per cell (thus “primary” cilium). Unlike motile cilia that beat rhythmically, primary cilia are missing a central pair of microtubules and thus act as immotile sensory organelles. Sometime referred to as “the cell’s antenna”, the primary cilium contains proteins that are not found anywhere else in the cell and has been found to regulate many critically important signaling pathways. Furthermore, the basal body that forms the base of the primary cilium is required for spindle formation in cellular mitosis, so the primary cilium must be disassembled and reassembled with every round of cell division. Numerous studies have implicated defective primary cilia assembly and signaling in a large variety of diseases, sometimes grouped together as “ciliopathies.” This includes polycystic kidney disease, which results from defective cilia signaling in renal tubular cells. We have shown the exocyst contributes to primary cilia assembly in these renal cells, and we continue to investigate the mechanisms by which cells regulate exocyst-mediated trafficking of intracellular vesicles to the primary cilia, and the role this plays in human development and disease.

Select Publications

Xiaofeng Zuo, Sang-Ho Kwon, Michael G. Janech, Yujing Dang, Steven D. Lauson, Ben Fogelgren, Noemi Polgar, and Joshua H. Lipschutz. Primary cilia and the exocyst are linked to urinary extracellular vesicle production and content. Journal of Biological Chemistry, 294(50): 19099-19110, PMCID: PMC6916495, 2019.

Brent A. Fujimoto, Madison Young, Lamar Carter, Alina P.S. Pang, Michael J. Corley, Ben Fogelgren, and Noemi Polgar. The exocyst complex regulates insulin-stimulated glucose uptake of skeletal muscle cells. American Journal of Physiology – Endocrinology and Metabolism, 317(6): E957-E972, PMCID: PMC6962504, 2019

Diana B. Fulmer, Katelynn A. Toomer, Lilong Guo, Kelsey Moore, Janiece Glover, Rebecca Stairley, Glenn P. Lobo, Xiaofeng Zuo, Yujing Dang, Yanhui Su, Ben Fogelgren, Patrick Gerard, Dongjun Chung, Mahyar Heydarpour, Rupak D. Mukherjee, Simon C. Body, Russell A. Norris, and Joshua H. Lipschutz. Genetic association of the exocyst with bicuspid aortic valve disease. Circulation, 140(16): 1331-1341, PMCID: PMC6989054, 2019.

Deepak Nihalani, Ashish Solanki, Ehtesham Arif, Xiaofeng Zuo, Yujing Dang, Benjamin Fogelgren, Damian Fermin, Matthew Sampson, and Joshua Lipschutz. Disruption of the exocyst induces podocyte loss and dysfunction. Journal of Biological Chemistry, 294(26): 10104-10119, PMCID: PMC6664173, 2019.

Lori L. O’Brien, Quiyu Guo, Emad B. Samani, Joo-Seop Park, Sean M. Hasso, Young-Jin Lee, Kevin A. Peterson, Andrew Smith, Trudy M. Hong, Scott Lozanoff, Ben Fogelgren, Anton Valouev, and Andrew P. McMahon. Transcriptional regulatory control of mammalian nephron progenitors revealed by multi-factor cistromic analysis and genetic studies. PLOS Genetics, 14(1):e1007181, PMCID: PMC5805373, 2018.

Noemi Polgar and Ben Fogelgren. Regulation of cell polarity by exocyst-mediated trafficking. Cold Spring Harbor Perspectives in Biology, 10(3), PMCID: PMC5587355, 2018.

Amanda J. Lee, Noemi Polgar, Josephine A. Napoli, Vanessa H. Lui, Kadee-Kalia Tamashiro, Brent A. Fujimoto, Karen S. Thompson, and Ben Fogelgren. Fibroproliferative response to urothelial failure obliterates the ureter lumen in a mouse model of prenatal congenital obstructive nephropathy. Scientific Reports, 6, 31137, PMCID: PMC4980620, 2016.

Cecilia Seixas, Soo Young Choi, Noemi Polgar, Nicole L. Umberger, Michael P. East, Xiaofeng Zuo, Hugo Moreiras, Rania Ghossoub, Alexandre Benmerah, Richard A. Kahn, Ben Fogelgren, Tamara Caspary, Joshua H. Lipschutz, and Duarte C. Barral. Arl13b and the exocyst interact synergistically in ciliogenesis. Molecular Biology of the Cell, 27(2), 308-320, PMCID: PMC4713133, 2016.

Noemi Polgar, Amanda J. Lee, Vanessa H. Lui, and Ben Fogelgren. Sec10 and the exocyst are critical for renal epithelial ciliogenesis and monolayer homeostasis in vitro and in vivo. American Journal of Physiology: Cell Physiology, 309(3), C190-201, PMCID: PMC4525081, 2015.

Ben Fogelgren, Noemi Polgar, Vanessa H. Lui, Amanda J. Lee, Kadee-Kalia Tamashiro, Josephine A. Napoli, Chad Walton, Xiaofeng Zuo, and Joshua H. Lipschutz. Urothelial defects from targeted inactivation of exocyst Sec10 in mice cause ureteropelvic junction obstructions. PLOS One, 10(6), e0129346. PMCID: PMC4457632, 2015.

Ben Fogelgren#, Shin-Yi Lin#, Xiaofeng Zuo, Kimberly M. Jaffe, Kwan Moo Park, Ryan J. Reichert, P. Darwin Bell, Rebecca D. Burdine, and Joshua H. Lipschutz. Exocyst Sec10 interacts with polycystin-2 and knockdown causes PKD-phenotypes. PLOS Genetics, 7(4): e1001361. PMCID: PMC3072367, 2011. #co-first authors