Otx2 controls identity and fate of glutamatergic progenitors of the thalamus by repressing GABAergic differentiation.

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.

A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo.

Midbrain neurons synthesizing the neurotransmitter dopamine play a central role in the modulation of different brain functions and are associated with major neurological and psychiatric disorders. Despite the importance of these cells, the molecular mechanisms controlling their development are still poorly understood. The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons. Here, we show that Wnt1 regulates the genetic network, including Otx2 and Nkx2-2, that is required for the establishment of the midbrain dopaminergic progenitor domain during embryonic development. In addition, Wnt1 is required for the terminal differentiation of midbrain dopaminergic neurons at later stages of embryogenesis. These results identify Wnt1 as a key molecule in the development of midbrain dopaminergic neurons in vivo. They also suggest the Wnt1-controlled signaling pathway as a promising target for new therapeutic strategies in the treatment of Parkinson's disease.

The paired-type homeobox gene Dmbx1 marks the midbrain and pretectum.

We have isolated a paired-type homeobox gene Dmbx1, previously known as Atx (Development 128 (2001) 4789), from chick and mouse. Sequence similarity reveals that this gene is highly related to the Otx genes. Expression of Dmbx1 commences during gastrulation, when transcripts are detected in a crescent around the anterior neural plate. As development progresses, Dmbx1 marks the prospective midbrain and pretectum. Dmbx1 shares its caudal border of expression with Otx2, while expression is sharply delimited rostrally by the synencephalic-parencephalic boundary, later becoming restricted to the posterior synencephalon. At later stages, Dmbx1 is expressed in dynamic domains of the hindbrain and spinal cord. Additional sites of expression comprise stomodeal ectoderm and foregut endoderm, presomitic mesoderm, and the nasal pit.