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Background  The content and composition of cerebrospinal fluid (CSF) is determined in large part by the choroid plexus (CP) and specifically, a specialized epithelial cell (CPe) layer that responds to, synthesizes, and transports peptide hormones into and out of CSF. Together with ventricular ependymal cells, these CPe relay homeostatic signals throughout the central nervous system (CNS) and regulate CSF hydrodynamics. One new candidate signal is augurin, a newly recognized 14 kDa protein that is encoded by  esophageal cancer related gene-4  ( Ecrg4 ), a putative tumor suppressor gene whose presence and function in normal tissues remains unexplored and enigmatic. The aim of this study was to explore whether  Ecrg4  and its product augurin, can be implicated in CNS development and the response to CNS injury.    Methods   Ecrg4  gene expression in CNS and peripheral tissues was studied by  in situ  hybridization and quantitative RT-PCR. Augurin, the protein encoded by  Ecrg4 , was detected by immunoblotting, immunohistochemistry and ELISA. The biological consequence of augurin over-expression was studied in a cortical stab model of rat CNS injury by intra-cerebro-ventricular injection of an adenovirus vector containing the  Ecrg4  cDNA. The biological consequences of reduced augurin expression were evaluated by characterizing the CNS phenotype caused by  Ecrg4  gene knockdown in developing zebrafish embryos.    Results  Gene expression and immunohistochemical analyses revealed that, the CP is a major source of  Ecrg4  in the CNS and that  Ecrg4  mRNA is predominantly localized to choroid plexus epithelial (CPe), ventricular and central canal cells of the spinal cord. After a stab injury into the brain however, both augurin staining and  Ecrg4  gene expression decreased precipitously. If the loss of augurin was circumvented by over-expressing  Ecrg4 in vivo , BrdU incorporation by cells in the subependymal zone decreased. Inversely, gene knockdown of  Ecrg4  in developing zebrafish embryos caused increased proliferation of GFAP-positive cells and induced a dose-dependent hydrocephalus-like phenotype that could be rescued by co-injection of antisense morpholinos with  Ecrg4  mRNA.    Conclusion  An unusually elevated expression of the  Ecrg4  gene in the CP implies that its product, augurin, plays a role in CP-CSF-CNS function. The results are all consistent with a model whereby an injury-induced decrease in augurin dysinhibits target cells at the ependymal-subependymal interface. We speculate that the ability of CP and ependymal epithelium to alter the progenitor cell response to CNS injury may be mediated, in part by  Ecrg4 . If so, the canonic control of its promoter by DNA methylation may implicate epigenetic mechanisms in neuroprogenitor fate and function in the CNS.

fluids and barriers of the cns

Ecrg4 expression and its product augurin in the choroid plexus: impact on fetal brain development, cerebrospinal fluid homeostasis and neuroprogenitor cell response to CNS injury