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Cerebral Cortex Advance Access published online on July 8, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp134
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© 2009 The Authors
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Transforming Growth Factor β Promotes Neuronal Cell Fate of Mouse Cortical and Hippocampal Progenitors In Vitro and In Vivo: Identification of Nedd9 as an Essential Signaling Component

Tanja Vogel1, Sandra Ahrens1,2, Nicole Büttner1 and Kerstin Krieglstein1,2

1 Department of Neuroanatomy, Centre of Anatomy, Georg-August-University, 37075 Goettingen, Germany, 2 Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, 79104 Freiburg, Germany

Address correspondence to email: tvogel1{at}gwdg.de.

Transforming Growth Factor β (Tgfβ) and associated signaling effectors are expressed in the forebrain, but little is known about the role of this multifunctional cytokine during forebrain development. Using hippocampal and cortical primary cell cultures of developing mouse brains, this study identified Tgfβ-regulated genes not only associated with cell cycle exit of progenitors but also with adoption of neuronal cell fate. Accordingly, we observed not only an antimitotic effect of Tgfβ on progenitors but also an increased expression of neuronal markers in Tgfβ treated cultures. This effect was dependent upon Smad4. Furthermore, in vivo loss-of-function analyses using Tgfβ2–/–/Tgfβ3–/– double mutant mice showed the opposite effect of increased cell proliferation and fewer neurons in the cerebral cortex and hippocampus. Gata2, Runx1, and Nedd9 were candidate genes regulated by Tgfβ and known to be involved in developmental processes of neuronal progenitors. Using siRNA-mediated knockdown, we identified Nedd9 as an essential signaling component for the Tgfβ-dependent increase in neuronal cell fate. Expression of this scaffolding protein, which is mainly described as a signaling molecule of the β1-integrin pathway, was not only induced after Tgfβ treatment but was also associated with morphological changes of the Nestin-positive progenitor pool observed upon exposure to Tgfβ.

Key Words: cerebral cortex • differentiation • Hef1 • Nestin • progenitor

Tanja Vogel and Sandra Ahrens contributed equally.


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