Mundel Laboratory

General information

Peter Mundel, M.D.
Professor, Medicine, Cell Biology and Anatomy
Chief, Division of Molecular Medicine
Vice Chair for Research, Department of Medicine

Research Interests

• The synaptopodin family of actin-associated proteins in health and disease
• Cell biology and pathology of kidney podocytes

Keywords and Phrases

• Regulation of actin cytoskeleton by signaling networks
• Actin cytoskeleton and synaptic plasticity
• Actin cytoskeleton and proteinuria
• Podocytes and the innate immune system
• Myopodin and bladder cancer
• Myopodin in myocyte differentiation and Z-disc signaling
• Regulation of cell-cell and cell-matrix adhesion by B7-1/CD80

Contact Information

• Office location: Batchelor Bldg., 6th Fl, Room 626 (R-762)
  1580 NW 10th Avenue
  Miami, FL 33136
• Tel: (305) 243-2360
•  Fax: (305) 243-4338
• Lab Location: Batchelor Bldg. 6th Fl (R-762),
  1580 NW 10th Avenue
  Miami, FL 33136
• Tel: (305) 243-6588
• Fax: (305) 243-4338
• E-mail: PMundel@med.miami.edu
• Administrative Assistant: Zurama Rodriguez
  Tel: (305)-243-8092
  Email: ZRodriguez@med.miami.edu
• 
  

Members

Research

The synaptopodin family of actin-associated proteins in health and disease
In the center of our research activity is the functional characterization of the synaptopodin gene family of actin-associated proteins. Synaptopodin is the founding member of a novel class of proline-rich actin associated proteins expressed in specialized, highly dynamic cell compartment such a telencephalic dendrites and foot processes of renal podocytes. Synaptopodin deficient (synpo^-/-) mice lack the dendritic spine apparatus and display impaired activity-dependent long-term synaptic plasticity. In contrast, the ultrastructure of podocytes in synpo^-/- mice is normal but synpo^-/- mice display impaired recovery from protamine sulfate induced podocyte foot process effacement and lipopolysaccharide induced nephrotic syndrome. Synpo^-/- podocytes show impaired actin filament reformation in vitro.

Synaptopodin exists in three isoforms, neuronal Synpo-short (685 amino acids), renal Synpo-long (903 amino acids) and Synpo-T (181 amino acids). The C-terminus of Synpo-long is identical to Synpo-T. All three isoforms specifically interact with a-actinin and elongate a-actinin-induced actin filaments. Synpo^-/- mice lack Synpo-short and Synpo-long expression, but show an upregulation of Synpo-T protein expression in podocytes, however not in the brain. Gene silencing of Synpo-T abrogates stress fiber formation in synpo^-/- podocytes, demonstrating that Synpo-T serves as a backup for Synpo-long in synpo^-/- podocytes. In concert, synaptopodin regulates the actin bundling activity of a-actinin in highly dynamic cell compartments like podocyte foot processes and the dendritic spine apparatus.

Myopodin, the second member of the synaptopodin gene family, is a dual compartment protein that shows a differentiation and stress dependent re-localization between the sarcomeric Z-disc and the nucleus. Myopodin is a signaling protein in the heart and a tumor suppressor in human bladder cancer. Myopodin is a dual-compartment, actin-bundling protein that functions as a tumor suppressor in human bladder cancer. In muscle cells, myopodin redistributes between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced fashion. We have recently shown that importin alpha binding and the subsequent nuclear import of myopodin are regulated by the serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. These results establish a novel paradigm for the promotion of nuclear import by 14-3-3 binding. They provide a molecular explanation for the phosphorylation-dependent nuclear import of nuclear localization signal-containing cargo proteins.

Cell biology and pathology of podocytes
Another major focus in the lab is the cell biology and pathology of podocytes. Podocytes are highly differentiated cells, which play a crucial role in the physiology and pathology of the kidney glomerulus. Podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with urinary protein loss.

Recently we uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity that is independent of T-cells. We found that upregulation of B7-1 in podocytes contributes to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.

A combination of genetic, structural, molecular and cell biological approaches is employed to unravel the function of the synaptopodin gene family in cardiac development and remodeling, during synaptic plasticity and in the pathogenesis of bladder cancer. Another major goal is the characterization of kidney podocytes as a novel component of the innate immune system. Students can select projects from the following major research areas:

• Cell and molecular biological analysis of synaptopodin. This project includes the analysis of the phenotype of synpo^-/-, the functional characterization of synpo^-/- neurons and podocytes and the molecular biological characterization of synaptopodin as regulator of the actin cytoskeleton in highly motile cell compartments such as podocyte foot processes and dendritic spines.
• Cell and structural biological characterization of myopodin. This project includes the functional characterization of myopodin-deficient mice and the mechanistic analysis of myopodin as a tumor suppressor in bladder cancer. The role of myopodin in myocyte differentiation and intracellular signaling between the sarcomeric Z-disc and the nucleus. Identification and functional characterization of myopodin interacting proteins.
• The role of B7-1 in podocytes. This research area includes the functional analysis of B7-1 as an inducible modifier of the glomerular filter and the role of podocytes as a novel component of the innate immune system. The role of B7-1 as inducible regulator of cell-cell and cell-matrix adhesion.

Selected Publications

• Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P. The actin cytoskeleton of kidney podocytes is a direct target of the anti-proteinuric effect of cyclosporine A. Nat Med. 2008, 14: 931-9388. Published online: 24 August 2008
• Faul C, Dhume A, Schecter A, Mundel P. Ca2+/Calmodulin-Dependent Kinase II, and Calcineurin Regulate the Intracellular Trafficking of Myopodin between the Z-Disc and the Nucleus of Cardiac Myocytes. Mol Cell Biol. 2007 Dec;27(23):8215-8227. Epub 2007 Oct 8.
• Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007 Sep;17(9):428-37. Epub 2007 Sep 4. Review.
• Yanagida-Asanuma E, Asanuma K, Kim K, Donnelly M, Young Choi H, Hyung Chang J, Suetsugu S, Tomino Y, Takenawa T, Faul C, Mundel P. Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am J Pathol. 2007 Aug;171(2):415-27. Epub 2007 Jun 14.
• Asanuma K, Campbell KN, Kim K, Faul C, Mundel P. Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. Proc Natl Acad Sci U S A. 2007, June 12 104 (24): 10134-10139, Epub 2007, May 30.
• Huber TB, Kwoh C, Wu H, Asanuma K, Godel M, Hartleben B, Blumer KJ, Miner JH, Mundel P, Shaw AS. Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin. J Clin Invest. 2006 May 1;116(5):1337-1345. Epub 2006 Apr 20.
• Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006 Apr 16; [Epub ahead of print].
• Faul C, Hüttelmaier S, Oh J, Hachet V, Singer RH, Mundel P. Promotion of importin a mediated nuclear import by phosphorylation dependent binding of cargo protein to 14-3-3. J Cell Biol. 2005 May 9;169(3): 415-424.
• Asanuma K, Kim K, Oh J, Giardino L, Chabanis S, Faul C, Reiser J, Mundel P. Synaptopodin regulates the actin bundling activity of alpha-actinin in an isoform specific manner. J Clin Invest. 2005 May;115(5):1188-1198. Epub 2005 Apr 1.
• Reiser J, Oh J, Shirato I, Asanuma K, Hug A, Mundel TM, Honey K, Ishidoh K, Kominami E, Kreidberg JA, Tomino Y, and Mundel P. Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha-3 integrin. J Biol Chem. 2004 Aug 13; 279(33):34827-32. Epub 2004 Jun 14.
• Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004 May;113(10):1390-1397.