title: Esophageal cancer related gene-4 is a choroid plexus-derived injury response gene: evidence for a biphasic response in early and late brain injury.
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.
authors.affiliation: Department of Surgery, School of Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Sonia
authors.initials: S
authors.lastname: Podvin
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Gonzalez
authors.forename: Miles C
authors.initials: MC
authors.lastname: Miller
authors.forename: Xitong
authors.initials: X
authors.lastname: Dang
authors.forename: Hannah
authors.initials: H
authors.lastname: Botfield
authors.forename: John E
authors.initials: JE
authors.lastname: Donahue
authors.forename: Arwa
authors.initials: A
authors.lastname: Kurabi
authors.forename: Matthew
authors.initials: M
authors.lastname: Boissaud-Cooke
authors.forename: Ryan
authors.initials: R
authors.lastname: Rossi
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Leadbeater
authors.forename: Conrad E
authors.initials: CE
authors.lastname: Johanson
authors.forename: Raul
authors.initials: R
authors.lastname: Coimbra
authors.forename: Edward G
authors.initials: EG
authors.lastname: Stopa
authors.forename: Brian P
authors.initials: BP
authors.lastname: Eliceiri
authors.forename: Andrew
authors.initials: A
authors.lastname: Baird
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins
chemical_list: C476999:ECRG4 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins