Isoforms of the Erythropoietin receptor in dopaminergic neurons of the Substantia Nigra. Issue 4 (30th September 2016)

• Record Type: Journal Article
• Authors: Marcuzzi, Federica; Zucchelli, Silvia; Bertuzzi, Maria; Santoro, Claudio; Tell, Gianluca; Carninci, Piero; Gustincich, Stefano
• Is Part Of: Journal of neurochemistry. Volume 139:Issue 4(2016)
• Page Start: 596
• Page End: 609
• Publication Date: 2016-09-30
• Subjects: dopaminergic neurons -- erythropoietin -- erythropoietin receptor -- Parkinson's disease; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13757
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract : Selective degeneration of A9 dopaminergic neurons leads to Parkinson's disease. We apply genome‐wide promoter identification technologies to identify A9‐specific transcripts. In isolated A9 neurons, we identify new variants of erythropoietin receptor (DA‐EpoR). DA‐EpoR transcript encodes for a N‐terminal truncated receptor. Based on STAT5 phosphorylation assays, we show that the new variant of N‐terminally truncated EpoR acts as decoy when co‐expressed with the full‐length form. A similar isoform is also found in human. Abstract: Erythropoietin receptor (EpoR) regulates erythrocytes differentiation in blood. In the brain, EpoR has been shown to protect several neuronal cell types from cell death, including the A9 dopaminergic neurons (DA) of the Substantia Nigra ( SN ). These cells form the nigrostriatal pathway and are devoted to the control of postural reflexes and voluntary movements. Selective degeneration of A9 DA neurons leads to Parkinson's disease. By the use of nanoCAGE, a technology that allows the identification of Transcription Start Sites (TSSs) at a genome‐wide level, we have described the promoter‐level expression atlas of mouse A9 DA neurons purified with Laser Capture Microdissection (LCM). Here, we identify mRNA variants of the Erythropoietin Receptor (DA‐EpoR) transcribed from alternative TSSs. Experimental validation and full‐length cDNA cloning is integrated with gene expression analysis in the FANTOM5 database. In DA neurons, the EpoR gene encodes for a N‐terminal truncated receptor. Based on STAT5 phosphorylation assays, we show that the new variant of N‐terminally truncated EpoR acts as decoy when co‐expressed with the full‐length form. A similar isoform is also found in human. This work highlights new complexities in the regulation of Erythropoietin (EPO) signaling in the brain.