Professor
Pathology & Immunology
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Our laboratory studies the biological function of neurturin, persephin and GDNF, closely related neurotrophic factors that promote survival of multiple neuronal populations including dopaminergic neurons, which degenerate in Parkinson's disease, and motor neurons, which are affected in Lou Gehrig's disease. These factors signal through a receptor complex comprised of the Ret tyrosine kinase and members of a family of GPI-linked co-receptors termed GFRa receptors. We are investigating the role of these factors and their cognate receptors in the development and function of the nervous system. Toward this end, we are generating and analyzing mice deficient in these proteins, performing structure/function analysis and delineating their signaling pathways.
Second, we are studying the biological roles of Egr transcription factors. Through analysis of knockout mice, it is clear they regulate a variety of processes including female reproduction (Egr1/NGFI-A), male reproduction (Egr4/NGFI-C), muscle spindle formation (Egr3) and peripheral nerve myelination (Egr2/Krox20). We also have identified two corepressors, Nab1 and Nab2, that modulate activity of Egr proteins and hence the expression of Egr-regulated target genes. We are intensely investigating the Nab/Egr interaction in Schwann cells because mutations in Egr2 that prevent association with Nabs cause defects in Schwann cell differentiation and result in hypomyelinating neuropathy.
Finally, we are focusing on the development of prostate cancer. We are investigating the role of several genes, including Egr1, Nab2 and a homeodomain protein Nkx3.1, that have been implicated in the development and progression of prostate cancer. We also are using a variety of functional genomics techniques to identify additional gene products that may play a role in this disease.
Research Publications
Le N, Nagarajan R, Wang JY, Araki T, Schmidt RE, Milbrandt J (2005 Feb 15). Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination. Proc Natl Acad Sci U S A. 102 (7): 2596-601. Full Article >
Leitner ML, Wang LH, Osborne PA, Golden JP, Milbrandt J, Johnson EM Jr (2005 Feb). Expression and function of GDNF family ligands and receptors in the carotid body. Exp Neurol. 191 Suppl 1: S68-79. Full Article >
Enomoto H, Hughes I, Golden J, Baloh RH, Yonemura S, Heuckeroth RO, Johnson EM Jr, Milbrandt J (2004 Nov 18). GFRalpha1 expression in cells lacking RET is dispensable for organogenesis and nerve regeneration. Neuron. 44 (4): 623-36. Full Article >
Jain S, Naughton CK, Yang M, Strickland A, Vij K, Encinas M, Golden J, Gupta A, Heuckeroth R, Johnson EM Jr, Milbrandt J (2004 Nov). Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis. Development. 131 (21): 5503-13. Full Article >
Wilson RK, Ley TJ, Cole FS, Milbrandt JD, Clifton S, Fulton L, Fewell G, Minx P, Sun H, McLellan M, Pohl C, Mardis ER (2003). Mutational profiling in the human genome. Cold Spring Harb Symp Quant Biol. 68: 23-9. Full Article >
Araki T, Sasaki Y, Milbrandt J (2004 Aug 13). Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 305 (5686): 1010-3. Full Article >
Contact Info
Jeffrey Milbrandt, M.D., Ph.D.
Office Location: 101 Biotechnology Bldg.
Office Phone: 314-362-4651
Campus Box: 8118
Fax: 314-362-8756
jmilbrandt@wustl.edu
http://www.milbrandt.wustl.edu
