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The Journal of Neuroscience, April 13, 2005, 25(15):3889-3899; doi:10.1523/JNEUROSCI.3447-04.2005

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Development/Plasticity/Repair
Downregulation of Activating Transcription Factor 5 Is Required for Differentiation of Neural Progenitor Cells into Astrocytes

James M. Angelastro,^1 * Jeffrey L. Mason,^1,2 * Tatyana N. Ignatova,³ Valery G. Kukekov,³ George B. Stengren,¹ James E. Goldman,¹ and Lloyd A. Greene¹

¹Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, ²Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ³Departments of Neuroscience and Neurosurgery, McKnight Brain Institute, Shands Cancer Center, University of Florida, Gainesville, Florida 32610

The mechanisms that regulate neural progenitor cell differentiation are primarily unknown. The transcription factor activating transcription factor 5 (ATF5) is expressed in neural progenitors of developing brain but is absent from mature astrocytes and neurons. Here, we demonstrate that ATF5 regulates the conversion of ventricular zone (VZ) and subventricular zone (SVZ) neural progenitors into astrocytes. Constitutive ATF5 expression maintains neural progenitor cell proliferation and blocks their in vitro and in vivo differentiation into astrocytes. Conversely, loss of ATF5 function promotes cell-cycle exit and allows astrocytic differentiation in vitro and in vivo. CNTF, a promoter of astrocytic differentiation, downregulates endogenous ATF5, whereas constitutively expressed ATF5 suppresses CNTF-promoted astrocyte genesis. Unexpectedly, constitutive ATF5 expression in neonatal SVZ cells both in vitro and in vivo causes them to acquire properties and anatomic distributions of VZ cells. These findings identify ATF5 as a key regulator of astrocyte formation and potentially of the VZ to SVZ transition.

Key words: ATF5; neural progenitor cells; CNTF; astrocyte; ventricular zone; neuron

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Received Aug 20, 2004; revised March 4, 2005; accepted March 4, 2005.

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