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The Journal of Neuroscience, January 23, 2008, 28(4):914-922; doi:10.1523/JNEUROSCI.4327-07.2008

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Development/Plasticity/Repair
Constitutive EGFR Signaling in Oligodendrocyte Progenitors Leads to Diffuse Hyperplasia in Postnatal White Matter

Sanja Ivkovic,^1,2 Peter Canoll,¹ and James E. Goldman^1,2

¹Department of Pathology and the ²Center for Neurobiology and Behavior, Columbia University, New York, New York 10032

Correspondence should be addressed to Dr. Sanja Ivkovic, Department of Pathology, Columbia University, 630 West 168th Street, New York, NY 10032. Email: si2117{at}columbia.edu

Gliogenesis requires the careful orchestration of migration, differentiation, and proliferation of progenitors. Signaling through the epidermal growth factor receptor (EGFR) has been implicated in regulating these processes in a variety of cell types, including neural progenitors. By retroviral infection, we constitutively expressed an EGFR-GFP fusion protein in white matter glial progenitors at postnatal day 3 of the rat forebrain in vivo and analyzed the development of these cells over the subsequent 15 weeks. EGFR-GFP+ cells remained proliferative and migratory, gradually populating the brains ipsilateral and contralateral to the side of viral infection, but never differentiated into mature glia. The accumulation of these cells doubled the total cell density in white matter and led to a 10-fold increase in the abundance of glial progenitors, giving rise to a progenitor "hyperplasia." The marker profile of infected cells, NG2+, olig2+, PDGFR-+, nestin+, GFAP–, and CC1–, indicated a close resemblance to oligodendrocyte progenitors. Positive immunostaining for phosphorylated EGFR colocalized with punctate accumulation of EGFR-GFP, indicating that a subset of receptors was engaged in active signaling. Furthermore, EGF was required to observe phospho-tyrosine EGFR immunostaining of glial progenitors in culture. These observations suggest that constitutive EGFR expression can inhibit glial differentiation, but requires ligand as well.

Key words: epidermal growth factor receptor; glial progenitors; oligodendrocyte progenitors; white matter; glial differentiation; glial migration; glioma

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Received May 7, 2007; revised Dec. 5, 2007; accepted Dec. 12, 2007.

Correspondence should be addressed to Dr. Sanja Ivkovic, Department of Pathology, Columbia University, 630 West 168th Street, New York, NY 10032. Email: si2117{at}columbia.edu

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