RGD Reference Report - 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.

General

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.
Authors:	Gonzalez, Ana Maria Podvin, Sonia Lin, Shuh-Yow Miller, Miles C Botfield, Hannah Leadbeater, Wendy E Roberton, Andrew Dang, Xitong Knowling, Stuart E Cardenas-Galindo, Elena Donahue, John E Stopa, Edward G Johanson, Conrad E Coimbra, Raul Eliceiri, Brian P Baird, Andrew
Citation:	Gonzalez AM, etal., Fluids Barriers CNS. 2011 Jan 18;8(1):6. doi: 10.1186/2045-8118-8-6.
RGD ID:	14695077
Pubmed:	PMID:21349154 (View Abstract at PubMed)
PMCID:	PMC3042980 (View Article at PubMed Central)
DOI:	DOI:10.1186/2045-8118-8-6 (Journal Full-text)
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.

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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Ecrg4	Rat	central nervous system development	involved_in	ISS	UniProtKB:Q566V9	PMID:21349154	UniProt
Ecrg4	Rat	negative regulation of cell population proliferation	involved_in	IMP		PMID:21349154	UniProt
Ecrg4	Rat	response to wounding	involved_in	IMP		PMID:21349154	UniProt

Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Ecrg4	Rat	apical plasma membrane	located_in	ISS	UniProtKB:Q9H1Z8-PRO_0000250514	PMID:21349154	UniProt
Ecrg4	Rat	cytoplasm	located_in	ISS	UniProtKB:Q9H1Z8-PRO_0000250514	PMID:21349154	UniProt
Ecrg4	Rat	extracellular space	located_in	IDA		PMID:21349154	UniProt

Objects Annotated

Genes (Rattus norvegicus)

Ecrg4 (ECRG4 augurin precursor)

Additional Information

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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.