Esophageal cancer related gene-4 is a choroid plexus-derived injury response gene: Evidence for a biphasic response in early and late brain injury

Sonia Podvin, Ana Maria Gonzalez, Miles C. Miller, Xitong Dang, Hannah Botfield, John E. Donahue, Arwa Kurabi, Matthew Boissaud-Cooke, Ryan Rossi, Wendy E. Leadbeater, Conrad E. Johanson, Raul Coimbra, Edward G. Stopa, Brian P. Eliceiri, Andrew Baird*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

By virtue of its ability to regulate the composition of cerebrospinal fluid (CSF), the choroid plexus (CP) is ideally suited to instigate a rapid response to traumatic brain injury (TBI) by producing growth regulatory proteins. For example, Esophageal Cancer Related Gene-4 (Ecrg4) is a tumor suppressor gene that encodes a hormone-like peptide called augurin that is present in large concentrations in CP epithelia (CPe). Because augurin is thought to regulate senescence, neuroprogenitor cell growth and differentiation in the CNS, we evaluated the kinetics of Ecrg4 expression and augurin immunoreactivity in CPe after CNS injury. Adult rats were injured with a penetrating cortical lesion and alterations in augurin immunoreactivity were examined by immunohistochemistry. Ecrg4 gene expression was characterized by in situ hybridization. Cell surface augurin was identified histologically by confocal microscopy and biochemically by sub-cellular fractionation. Both Ecrg4 gene expression and augurin protein levels were decreased 24-72 hrs post-injury but restored to uninjured levels by day 7 post-injury. Protein staining in the supraoptic nucleus of the hypothalamus, used as a control brain region, did not show a decrease of auguin immunoreactivity. Ecrg4 gene expression localized to CPe cells, and augurin protein to the CPe ventricular face. Extracellular cell surface tethering of 14 kDa augurin was confirmed by cell surface fractionation of primary human CPe cells in vitro while a 6-8 kDa fragment of augurin was detected in conditioned media, indicating release from the cell surface by proteolytic processing. In rat CSF however, 14 kDa augurin was detected. We hypothesize the initial release and proteolytic processing of augurin participates in the activation phase of injury while sustained Ecrg4 down-regulation is dysinhibitory during the proliferative phase. Accordingly, augurin would play a constitutive inhibitory function in normal CNS while down regulation of Ecrg4 gene expression in injury, like in cancer, dysinhibits proliferation.

Original languageEnglish
Article numbere24609
JournalPLoS ONE
Volume6
Issue number9
DOIs
Publication statusPublished - 14 Sep 2011

Bibliographical note

© 2011 Podvin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    Podvin, S., Gonzalez, A. M., Miller, M. C., Dang, X., Botfield, H., Donahue, J. E., Kurabi, A., Boissaud-Cooke, M., Rossi, R., Leadbeater, W. E., Johanson, C. E., Coimbra, R., Stopa, E. G., Eliceiri, B. P., & Baird, A. (2011). Esophageal cancer related gene-4 is a choroid plexus-derived injury response gene: Evidence for a biphasic response in early and late brain injury. PLoS ONE, 6(9), [e24609]. https://doi.org/10.1371/journal.pone.0024609