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The Journal of Neuroscience, June 1, 2003, 23(11):4590-4600
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Regulated Expression of ATF5 Is Required for the Progression of Neural Progenitor Cells to Neurons
James M. Angelastro,1,3
Tatyana N. Ignatova,4,5
Valery G. Kukekov,4,5
Dennis A. Steindler,4,5
George B. Stengren,1,3
Cathy Mendelsohn,1,2,3 and
Lloyd A. Greene1,3
1 Department of Pathology, Columbia University College of Physicians and
Surgeons, New York, New York 10032,
2 Department of Urology, Columbia University College of Physicians and Surgeons,
New York, New York 10032,
3 Department of Center for Neurobiology and Behavior, Columbia University
College of Physicians and Surgeons, New York, New York 10032,
4 Department of Neuroscience, McKnight Brain Institute, Shands Cancer Center,
University of Florida, Gainesville, Florida 32610, and
5 Department of Neurosurgery, McKnight Brain Institute, Shands Cancer Center,
University of Florida, Gainesville, Florida 32610
An important milestone in brain development is the transition of
neuroprogenitor cells to postmitotic neurons. We report that the bZIP
transcription factor ATF5 plays a major regulatory role in this process. In
developing brain ATF5 expression is high within ventricular zones containing
neural stem and progenitor cells and is undetectable in postmitotic neurons.
In attached clonal neurosphere cultures ATF5 is expressed by neural
stem/progenitor cells and is undetectable in tau-positive neurons. In PC12
cell cultures nerve growth factor (NGF) dramatically downregulates endogenous
ATF5 protein and transcripts, whereas exogenous ATF5 suppresses NGF-promoted
neurite outgrowth. Such inhibition requires the repression of CRE sites. In
contrast, loss of function conferred by dominant-negative ATF5 accelerates
NGF-promoted neuritogenesis. Exogenous ATF5 also suppresses, and
dominant-negative ATF5 and a small-interfering RNA targeted to ATF5 promote,
neurogenesis by cultured nestin-positive telencephalic cells. These findings
indicate that ATF5 blocks the differentiation of neuroprogenitor cells into
neurons and must be downregulated to permit this process to occur.
Key words: ATF5; neural progenitor cells; NGF; neuron; differentiation; ventricular zone
Received Nov. 1, 2002;
revised Mar. 10, 2003;
accepted Mar. 10, 2003.
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