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Journal of Neuroscience, Vol 15, 4992-5003, Copyright © 1995 by Society for Neuroscience
Expression, secretion, and age-related downregulation of pigment epithelium-derived factor, a serpin with neurotrophic activity
J Tombran-Tink, SM Shivaram, GJ Chader, LV Johnson and D Bok
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Retinal pigment epithelial (RPE) cells form a functional complex with
photoreceptor neurons of the retina, interacting through the
interphotoreceptor matrix (IPM). We now provide evidence that the gene for
pigment epithelium-derived factor (PEDF), a protein possessing neurotrophic
and neuronal-survival activities, is highly expressed by both fetal and
young adult RPE cells. PEDF mRNA is present in RPE cells of the human eye
at 17 weeks of gestation, demonstrating its potential for action in vivo
during early retinal development. The PEDF protein is secreted in vivo
where it constitutes a part of the fetal and adult IPM surrounding
photoreceptor outer segments. A polyclonal PEDF antibody recognizes at
least four isoforms of secreted human and bovine PEDF by two dimensional
gel analysis, and detects a similar 50 kDa protein in the IPM of several
other vertebrate species. Within soluble extracts of RPE cells, however,
where little, if any, of the 50 kDa species can be detected, an
immunoreactive 36 kDa protein is observed by Western blot analysis. By
immunofluorescence, PEDF is localized intracellularly in association with
the nucleus, presumptive secretory granules, and cytoskeletal elements of
cultured RPE cells with PEDF and actin antibodies colocalizing to the same
cytoskeletal structures. During initial stages of attachment, PEDF and
actin also concentrate at the tips of pseudopods extended by the cultured
RPE cells. However, with successive passages, synthesis, and secretion of
the PEDF protein as well as transcription of its mRNA decrease and are lost
by about 10 passages. In parallel, cultured RPE cells lose their
proliferative potential and change from an epithelial-like morphology in
early passages to a more fibroblast-like appearance by about the 10th
passage. PEDF is thus apparently present intracellularly and
extracellularly in both fetal and early adult periods where it could be
involved in cellular differentiation and survival and with its loss, in the
onset of senescence.
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