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J. Biol. Chem., Vol. 279, Issue 40, 41839-41845, October 1, 2004

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Microglia-derived Pronerve Growth Factor Promotes Photoreceptor Cell Death via p75 Neurotrophin Receptor^*

Bhooma Srinivasan, Criselda H. Roque, Barbara L. Hempstead¶, Muayyad R. Al-Ubaidi||, and Rouel S. Roque**

From the Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas 76107, the ^¶Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, and the ^||Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Reports implicating microglia-derived nerve growth factor (NGF) during programmed cell death in the developing chick retina led us to investigate its possible role in degenerative retinal disease. Freshly isolated activated retinal microglia expressed high molecular weight forms of neurotrophins including that of nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. Conditioned media from cultured retinal microglia (MGCM) consistently yielded a 32-kDa NGF-reactive band when supplemented with bovine serum albumin (BSA) or protease inhibitors (PI); and promoted cell death that was suppressed by NGF immunodepletion in a mouse photoreceptor cell line (661w). The 32 kDa protein was partially purified (MGCM/p32) and was highly immunoreactive with a polyclonal anti-pro-NGF antibody. Both MGCM/p32 and recombinant pro-NGF protein promoted cell death in 661w cultures. Increased levels of pro-NGF mRNA and protein were observed in the RCS rat model of retinal dystrophy. MGCM-mediated cell death was reversed by p75NTR antiserum in p75NTR⁺/trkA^– 661w cells. Our study shows that a 32 kDa pro-NGF protein released by activated retinal microglia promoted degeneration of cultured photoreceptor cells. Moreover, our study suggests that defective post-translational processing of NGF might be involved in photoreceptor cell loss in retinal dystrophy.

Received for publication, March 15, 2004 , and in revised form, July 19, 2004.

^* This work was supported by National Institutes of Health Grant EY10766 (to R. S. R.), a University of North Texas Health Science Center at Fort Worth Faculty research grant (to R. S. R.), and National Institutes of Health Grant NS30687 (to B. L. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work was taken in part from a dissertation submitted to the University of North Texas Health Science Center at Fort Worth in partial fulfillment of the requirements for the degree Doctor of Philosophy.

^** To whom correspondence should be addressed: Dept. of Cell Biology and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, Texas 76107-2699. Tel.: 817-735-5055; Fax: 817-735-2610; E-mail: rroque{at}hsc.unt.edu.

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