title: Otx2 controls identity and fate of glutamatergic progenitors of the thalamus by repressing GABAergic differentiation.
abstract: 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.
authors.affiliation: Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Puelles
authors.forename: Dario
authors.initials: D
authors.lastname: Acampora
authors.forename: Robindra
authors.initials: R
authors.lastname: Gogoi
authors.forename: Francesca
authors.initials: F
authors.lastname: Tuorto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Papalia
authors.forename: Francois
authors.initials: F
authors.lastname: Guillemot
authors.forename: Siew-Lan
authors.initials: SL
authors.lastname: Ang
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D018756:GABA Antagonists; D018698:Glutamic Acid / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D009474:Neurons / Q000502:physiology; D051857:Otx Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D013788:Thalamus / Q000166:cytology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D018756:GABA Antagonists; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid