Abstract
In-vitro expanded neural stem cells (NSCs) of the adult subependymal zone (SEZ) may serve as a source for replacing degenerating neurones in disease and trauma. Crucial for the viability of this approach is the ability to selectively generate specific types of neurones from these cells. Here we show that NSCs derived from the adult mouse SEZ and expanded in vitro as neurosphere cells lose their in-vivo specification and generate a mixture of progeny comprising both GABAergic and also, surprisingly, glutamatergic neurones. When forced to express the pro-neural transcription factor neurogenin 2, virtually all progeny of in-vitro expanded adult NSCs acquire a glutamatergic identity, whereas only GABAergic neurones are generated upon expression of the transcription factor Mash1. Respecification of expanded NSCs from the adult SEZ by neurogenin 2 was accompanied by upregulation of the T-box transcription factor Tbr1, suggesting that their progeny had acquired a dorsal telencephalic identity. Thus, in-vitro expanded adult NSCs have the competence to become directed towards distinct functional neurotransmitter phenotypes when the appropriate transcriptional cues are provided.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult Stem Cells / cytology
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Adult Stem Cells / drug effects
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Adult Stem Cells / metabolism*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Basic Helix-Loop-Helix Transcription Factors / pharmacology
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Cell Culture Techniques / methods
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Cell Differentiation / drug effects
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Cell Differentiation / genetics*
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Cell Lineage / drug effects
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Cell Lineage / genetics*
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Cell Separation / methods
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Cells, Cultured
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DNA-Binding Proteins / genetics
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Excitatory Amino Acid Antagonists / pharmacology
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GABA Antagonists / pharmacology
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Glutamic Acid / metabolism
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Mice
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Mice, Inbred C57BL
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / pharmacology
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Neurotransmitter Agents / metabolism*
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Phenotype
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Spheroids, Cellular / cytology
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Spheroids, Cellular / drug effects
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Spheroids, Cellular / metabolism
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T-Box Domain Proteins
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Telencephalon / cytology
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Telencephalon / embryology*
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Transcriptional Activation / drug effects
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Transcriptional Activation / genetics
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gamma-Aminobutyric Acid / metabolism
Substances
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Ascl1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Excitatory Amino Acid Antagonists
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GABA Antagonists
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Nerve Tissue Proteins
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Neurog2 protein, mouse
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Neurotransmitter Agents
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T-Box Domain Proteins
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Tbr1 protein, mouse
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Glutamic Acid
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gamma-Aminobutyric Acid