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.

Otx genes in the evolution of the vertebrate brain.

Only until a decade ago, animal phylogeny was traditionally based on the assumption that evolution of bilaterians went from simple to complex through gradual steps in which the extant species would represent grades of intermediate complexity that reflect the organizational levels of their ancestors. The advent of more sophisticated molecular biology techniques combined to an increasing variety of functional experiments has provided new tools, which lead us to consider evolutionary studies under a brand new light. An ancestral versus derived low-complexity of a given organism has now to be carefully re-assessed and also the molecular data so far accumulated needs to be re-evaluated. Conserved gene families expressed in the nervous system of all the species have been extensively used to reconstruct evolutionary steps, which may lead to identify the morphological as well as molecular features of the last common ancestor of bilaterians (Urbilateria). The Otx gene family is among these and will be here reviewed.