Media type: E-Article Title: The axon guidance molecule Netrin‐4 is expressed by Müller cells and contributes to angiogenesis in the retina Contributor: Lange, Johannes; Yafai, Yousef; Noack, André; Yang, Xiu Mei; Munk, Anne‐Britta; Krohn, Sandra; Iandiev, Ianors; Wiedemann, Peter; Reichenbach, Andreas; Eichler, Wolfram imprint: Wiley, 2012 Published in: Glia Language: English DOI: 10.1002/glia.22376 ISSN: 1098-1136; 0894-1491 Keywords: Cellular and Molecular Neuroscience ; Neurology Origination: Footnote: Description: <jats:title>Abstract</jats:title><jats:p>Retinal glial (Müller) cells are involved in a wide range of developmental mechanisms, including axon guidance and angiogenesis. This study was undertaken to explore whether Netrin‐4, an axonal guidance molecule, is expressed by Müller cells and promotes angiogenesis‐related activities. Netrin‐4 was found through all retinal layers, and its expression was demonstrated in Müller cells, retinal pigment epithelium cells and bovine retinal endothelial cells (BRECs). Co‐localization of Netrin‐4 with Müller cell‐specific molecules [cellular retinaldehyde‐binding protein (cRALBP), vimentin] was observed in the ganglion cell layer, nerve fiber layer, and at the outer limiting membrane. Under hypoxic conditions, the release of Netrin‐4 from Müller cells was increased, with mRNA levels upregulated in a hypoxia‐inducible factor‐1‐dependent manner and dependent on the concomitantly induced release of vascular endothelial growth factor. These findings were consistent with an intensified immunofluorescence of Netrin‐4 labeling in the postischemic retinas after ischemia‐reperfusion. Netrin‐4 stimulated BRECs to increase phosphorylation of the mitogen‐activated protein (MAP) kinases, extracellular signal‐regulated kinase (ERK)‐1/‐2, and p38, in a dose‐dependent manner. Synthetic inhibitors of the MAP kinases were able to suppress Netrin‐4‐induced migration and proliferation of BRECs suggesting that both MAP kinases are differentially involved in Netrin‐4‐induced angiogenesis. Two receptors for Netrins, i.e., deleted in colorectal cancer (DCC) and uncoordinated‐5‐homolog 1 (Unc5H1), were detected in BRECs. DCC is at least partially required for Netrin‐4‐induced activation of ERK‐1/‐2. These data suggest that Müller glial cells contribute to, and may modulate, retinal Netrin‐4 levels. This may be a novel pathway of Müller cell‐mediated control of retinal angiogenesis, particularly under hypoxic/ischemic conditions when the cells upregulate Netrin‐4 expression. © 2012 Wiley Periodicals, Inc.</jats:p>