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The Journal of Neuroscience, May 31, 2006, 26(22):5955-5964; doi:10.1523/JNEUROSCI.1097-06.2006

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Development/Plasticity/Repair
Otx2 Controls Identity and Fate of Glutamatergic Progenitors of the Thalamus by Repressing GABAergic Differentiation

Eduardo Puelles,¹ Dario Acampora,^1,2,4 Robindra Gogoi,¹ Francesca Tuorto,^2,4 Alessandro Papalia,¹ Francois Guillemot,⁵ Siew-Lan Ang,⁵ and Antonio Simeone^1,2,3,4

¹Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom, ²CEINGE Biotecnologie Avanzate, 80145 Naples, Italy, ³Scuola Europea di Medicina Molecolare, 80145 Naples, Italy, ⁴Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, 80131 Naples, Italy, and ⁵Division of Developmental Neurobiology, National Institute for Medical Research, London NW7 1AA, United Kingdom

Correspondence should be addressed to Antonio Simeone, CEINGE Biotecnologie Aranzate, Via Comunale Margherita 482, 80145 Naples, Italy. Email: antonio.simeone{at}kcl.ac.uk

GABAergic and glutamatergic neurons modulate inhibitory and excitatory networks in the CNS, and their impairment may cause neurological and psychiatric disorders. Thus, understanding the molecular mechanisms that control neurotransmitter phenotype and identity of excitatory and inhibitory progenitors has considerable relevance. Here we investigated the consequence of Otx2 (orthodenticle homolog) ablation in glutamatergic progenitors of the dorsal thalamus (referred to as thalamus). We report that Otx2 is cell-autonomously required in these progenitors to repress GABAergic differentiation. Our data indicate that Otx2 may prevent GABAergic fate switch by repressing the basic helix–loop–helix gene Mash1 (mammalian achaete-schute homolog) in progenitors expressing Ngn2 (neurogenin homolog). The lack of Otx2 also resulted in the activation of Pax3 (paired box gene), Pax7, and Lim1 (Lin-11/Isl-1/Mec-3), three genes normally coexpressed with Mash1 and GABAergic markers in the pretectum, thus suggesting that thalamic progenitors lacking Otx2 exhibit marker similarities with those of the pretectum. Furthermore, Otx2 ablation gave rise to a marked increase in proliferating activity of thalamic progenitors and the formation of hyperplastic cell masses. Thus, this study provides evidence for a novel and crucial role of Otx2 in the molecular mechanism by which identity and fate of glutamatergic precursors are established in the thalamus. Our data also support the concept that proper assignment of identity and fate of neuronal precursors occurs through the suppression of alternative differentiation programs.

Key words: Otx2; neuronal differentiation; glutamatergic fate; GABAergic fate; proliferation; thalamus

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Received March 14, 2006; revised April 19, 2006; accepted April 19, 2006.

Correspondence should be addressed to Antonio Simeone, CEINGE Biotecnologie Aranzate, Via Comunale Margherita 482, 80145 Naples, Italy. Email: antonio.simeone{at}kcl.ac.uk

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