PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation

• Published in: Developmental neurobiology (Hoboken, N.J.) N.J.), 2007-09, Vol.67 (10), p.1348-1361
• Main Authors: Peltier, Joseph, O'Neill, Analeah, Schaffer, David V.
• Format: Article
• Language: English
• Subjects: adult neural hippocampal progenitor; Aging - physiology; Animals; Biomarkers; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Proliferation - drug effects; Cells, Cultured; CREB; Cyclic AMP Response Element-Binding Protein - metabolism; differentiation; Female; Glial Fibrillary Acidic Protein - metabolism; Hippocampus - cytology; Hippocampus - enzymology; Hippocampus - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Neurons - drug effects; Neurons - enzymology; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt; proliferation; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Inbred F344; Signal Transduction - physiology; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Tubulin - metabolism
• ISSN: 1932-8451; 1932-846X
• DOI: 10.1002/dneu.20506

The phosphoinositide 3‐OH kinase (PI3K)/Akt pathway has been implicated in regulating several important cellular processes, including apoptosis, survival, proliferation, and metabolism. Using both pharmacological and genetic means, we demonstrate here that PI3K/Akt plays a crucial role in the proliferation of adult hippocampal neural progenitor cells. PI3K/Akt transduces intracellular signals from multiple mitogens, including basic fibroblast growth factor (FGF‐2), Sonic hedgehog (Shh), and insulin‐like growth factor 1 (IGF‐1). In addition, retroviral vector‐mediated over‐expression of wild type Akt increased cell proliferation, while a dominant negative Akt inhibited proliferation. Furthermore, wild type Akt over‐expression reduced glial (GFAP) and neuronal (β‐tubulin III) marker expression during differentiation, indicating that it inhibits cell differentiation. We also show that activation of the cAMP response element binding protein (CREB), which occurs in cells stimulated by FGF‐2, is limited when Akt signaling is inhibited, demonstrating a link between Akt and CREB. Over‐expression of wild type CREB increases progenitor proliferation, whereas dominant negative CREB only slightly decreases proliferation. These results indicate that PI3K/Akt signaling integrates extracellular signaling information to promote cellular proliferation and inhibit differentiation in adult neural progenitors. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.