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The Journal of Neuroscience, August 8, 2007, 27(32):8654-8664; doi:10.1523/JNEUROSCI.1615-07.2007

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Development/Plasticity/Repair
Functional Properties of Neurons Derived from In Vitro Reprogrammed Postnatal Astroglia

Benedikt Berninger,^1,2 Marcos R. Costa,² Ursula Koch,³ Timm Schroeder,² Bernd Sutor,¹ Benedikt Grothe,³ and Magdalena Götz^1,2

¹Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, D-80336 Munich, Germany, ²Institute for Stem Cell Research, National Research Center for Environment and Health, D-85764 Neuherberg, Germany, and ³Department Biologie II, Division of Neurobiology, Ludwig-Maximilians University Munich, D-82152 Planegg-Martinsried, Germany

Correspondence should be addressed to either Dr. Magdalena Götz or Dr. Benedikt Berninger, Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Schillerstrasse 46, D-80336 Munich, Germany. Email: magdalena.goetz{at}gsf.de or Email: benedikt.berninger{at}gsf.de

With the exception of astroglia-like cells in the neurogenic niches of the telencephalic subependymal or hippocampal subgranular zone, astroglia in all other regions of the adult mouse brain do not normally generate neurons. Previous studies have shown, however, that early postnatal cortical astroglia in culture can be reprogrammed to adopt a neuronal fate after forced expression of Pax6, a transcription factor (TF) required for proper neuronal specification during embryonic corticogenesis. Here we show that also the proneural genes neurogenin-2 and Mash1 (mammalian achaete schute homolog 1) possess the ability to reprogram astroglial cells from early postnatal cerebral cortex. By means of time-lapse imaging of green fluorescent astroglia, we provide direct evidence that it is indeed cells with astroglial characteristics that give rise to neurons. Using patch-clamp recordings in culture, we show that astroglia-derived neurons acquire active conductances and are capable of firing action potentials, thus displaying hallmarks of true neurons. However, independent of the TF used for reprogramming, astroglia-derived neurons appear to mature more slowly compared with embryonic-born neurons and fail to generate a functional presynaptic output within the culturing period. However, when cocultured with embryonic cortical neurons, astroglia-derived neurons receive synaptic input, demonstrating that they are competent of establishing a functional postsynaptic compartment. Our data demonstrate that single TFs are capable of inducing a remarkable functional reprogramming of astroglia toward a truly neuronal identity.

Key words: stem cells; neurogenesis; astrocyte (astroglia); transcription factor; gene transfer; regeneration

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Received Dec. 12, 2006; revised June 6, 2007; accepted June 7, 2007.

Correspondence should be addressed to either Dr. Magdalena Götz or Dr. Benedikt Berninger, Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Schillerstrasse 46, D-80336 Munich, Germany. Email: magdalena.goetz{at}gsf.de or Email: benedikt.berninger{at}gsf.de

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