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Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinsons disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the transcription factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors. By using mouse models and immunohistochemistry, we have investigated whether Otx2 is expressed also in post-mitotic mdDA neurons. Our data reveal that Otx2 is expressed in post-mitotic mesDA neurons during mid-late gestation and in the adult brain. Remarkably, Otx2 expression is sharply excluded from mdDA neurons of the SN and is restricted to a relevant fraction of VTA neurons. Otx2+-TH+ neurons are concentrated to the ventral part of the VTA. Combined expression with other regionalized VTA markers shows that Otx2+-TH+ neurons are prevalently Girk2- and Calb+ and among these, those located in the medial and ventralmost portion of the VTA are also Ahd2+. These findings indicate that Otx2 represents the first transcription factor with a proven role in mdDA neurogenesis whose expression discriminates between SN and a relevant proportion of VTA neurons. This supports the possibility that Otx2 may act as a post-mitotic selector controlling functional features (e.g. identity and/or survival) of a relevant fraction of VTA neurons in the adult.

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.

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., (Copyright 2002 Elsevier Science Ireland Ltd.)

Over the past few years, a huge amount of work has provided mouse mutants for many genes required for regionalization of the developing brain. This remarkable work now offers the opportunity of unmasking new and unexpected gene functions that underlie a complex network of molecular interactions.

Neurons usually migrate and differentiate in one particular encephalic vesicle. We identified a murine population of diencephalic neurons that colonized the telencephalic amygdaloid complex, migrating along a tangential route that crosses a boundary between developing brain vesicles. The diencephalic transcription factor OTP was necessary for this migratory behavior. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Otx1 belongs to the paired class of homeobox genes and plays a pivotal role in brain development. Here, we show that Otx1 is expressed in hematopoietic pluripotent and erythroid progenitor cells. Moreover, bone marrow cells from mice lacking Otx1 exhibit a cell-autonomous impairment of the erythroid compartment. In agreement with these results, molecular analysis revealed decreased levels of erythroid genes that include the SCL and GATA-1 transcription factors. Accordingly, a gain of function of SCL rescues the erythroid deficiency in Otx1[sup -/-] mice. Taken together, our findings indicate a function for Otx1 in the regulation of blood cell production. [ABSTRACT FROM AUTHOR]

In the last decade, a number of genes related to the induction, specification and regionalization of the brain were isolated and their functional properties currently are being dissected. Among these, Otx1 and Otx2 play a pivotal role in several processes of brain morphogenesis. Findings from several groups now confirm the importance of Otx2 in the early specification of neuroectoderm destined to become fore—midbrain, the existence of an Otx gene dosage-dependent mechanism in patterning the developing brain, and the involvement of Otx1 in corticogenesis. Some of these properties appear particularly fascinating when considered in evolutionary terms and highlight the central role of Otx genes in the establishment of the genetic program defining the complexity of a vertebrate brain. This review deals with the major aspects related to the roles played by Otx1 and Otx2 in the development and evolution of the mammalian brain. [ABSTRACT FROM AUTHOR]

One of the earliest organizational decisions in the development of the vertebrate brain is the division of the neural plate into Otx2-positive anterior and Gbx2-positive posterior territories. At the junction of these two expression domains, a local signaling center is formed, known as the midbrain-hindbrain boundary (MHB). This tissue coordinates or "organizes" the development of neighboring brain structures, such as the midbrain and cerebellum. Correct positioning of the MHB is thought to depend on mutual repression involving these two homeobox genes. Using a cell culture colocalization assay and coimmunoprecipitation experiments, we show that engrailed homology region 1 (eh1)-like motifs of both transcription factors physically interact with the WD40 domain of Groucho/Tle corepressor proteins. In addition, heat shock-induced expression of wild-type and mutant Otx2 and Gbx2 in medaka embryos demonstrates that Groucho is required for the repression of Otx2 by Gbx2. On the other hand, the repressive functions of Otx2 on Gbx2 do not appear to be dependent on corepressor interaction. Interestingly, the association of Groucho with Otx2 is also required for the repression of Fgf8 in the MHB. Therefore Groucho/Tle family members appear to regulate key aspects in the MHB development of the vertebrate brain. [ABSTRACT FROM AUTHOR]