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Previous studies have reported that the activities of the hepatocyte growth factor (HGF) and its receptor, the Met tyrosine kinase, are mediated by specific downstream signaling pathways. Herein, replacement of the wild-type Met receptor with signaling mutants produced phenotypes characteristic of those produced by met and hgf null mutants such as embryonal death and placenta, liver and limb muscle defects. It was suggested that Met could be required to mediate a pathway in late myogenesis.

We had previously reported that in gastrulating mouse embryos retinoic acid (RA) induces morphological as well molecular alterations strictly depending on the time of administration. In particular, embryos treated with RA at the mid-late streak stage share reduction of the rostral central nervous system (CNS) and increase of the hindbrain. In the same embryos, loss of the forebrain-expressed genes, such as Emx1, Emx2, and Dlx1, and rostral ectopic expression of the Hoxb-1 gene suggest an antero-posterior (A/P) ordered repatterning of the fore-, mid-, and hindbrain regions. Several genes, such as Pax-2, Wnt-1, En-2, and En-1, are involved in the establishment of midbrain and rostral hindbrain regional identities and boundaries. We report that these genes become coordinately anteriorized only in embryos treated with RA at the late streak stage. Moreover, in the hindbrain of the same embryos, at 8.5 days post coitum (dpc), Wnt-1 and Pax-2 are rostrally induced all along the neural plate. Considering that forebrain markers are repressed in embryos treated with RA at the same time, these findings strongly support the idea that RA administration at the late streak stage induces an ordered repatterning of the rostral CNS, possibly altering the A/P nature of mesendodermal inductive signals.

Summary Mouse embryonic stem cells (ESCs) and the inner cell mass (ICM)-derived epiblast exhibit naive pluripotency. ESC-derived epiblast stem cells (EpiSCs) and the postimplantation epiblast exhibit primed pluripotency. Although core pluripotency factors are well-characterized, additional regulators, including Otx2, recently have been shown to function during the transition from naive to primed pluripotency. Here we uncover a role for Otx2 in the control of the naive pluripotent state. We analyzed Otx2-binding activity in ESCs and EpiSCs and identified Nanog, Oct4, and Sox2 as direct targets. To unravel the Otx2 transcriptional network, we targeted the strongest Otx2-binding site in the Nanog promoter, finding that this site modulates the size of specific ESC-subtype compartments in cultured cells and promotes Nanog expression in vivo, predisposing ICM differentiation to epiblast. Otx2-mediated Nanog regulation thus contributes to the integrity of the ESC state and cell lineage specification in preimplantation development. [ABSTRACT FROM AUTHOR]

Summary OTX2 (orthodenticle homeobox 2) haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2 +/GFP heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2 +/GFP mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2 +/GFP mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy. [ABSTRACT FROM AUTHOR]

Summary Distinct midbrain dopamine (mDA) neuron subtypes are found in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), but it is mainly SNc neurons that degenerate in Parkinson’s disease. Interest in how mDA neurons develop has been stimulated by the potential use of stem cells in therapy or disease modeling. However, very little is known about how specific dopaminergic subtypes are generated. Here, we show that the expression profiles of the transcription factors Sox6, Otx2, and Nolz1 define subpopulations of mDA neurons already at the neural progenitor cell stage. After cell-cycle exit, Sox6 selectively localizes to SNc neurons, while Otx2 and Nolz1 are expressed in a subset of VTA neurons. Importantly, Sox6 ablation leads to decreased expression of SNc markers and a corresponding increase in VTA markers, while Otx2 ablation has the opposite effect. Moreover, deletion of Sox6 affects striatal innervation and dopamine levels. We also find reduced Sox6 levels in Parkinson’s disease patients. These findings identify Sox6 as a determinant of SNc neuron development and should facilitate the engineering of relevant mDA neurons for cell therapy and disease modeling. [ABSTRACT FROM AUTHOR]

Summary: JMJD3 (KDM6B) antagonizes Polycomb silencing by demethylating lysine 27 on histone H3. The interplay of methyltransferases and demethylases at this residue is thought to underlie critical cell fate transitions, and the dynamics of H3K27me3 during neurogenesis posited for JMJD3 a critical role in the acquisition of neural fate. Despite evidence of its involvement in early neural commitment, however, its role in the emergence and maturation of the mammalian CNS remains unknown. Here, we inactivated Jmjd3 in the mouse and found that its loss causes perinatal lethality with the complete and selective disruption of the pre-Bötzinger complex (PBC), the pacemaker of the respiratory rhythm generator. Through genetic and electrophysiological approaches, we show that the enzymatic activity of JMJD3 is selectively required for the maintenance of the PBC and controls critical regulators of PBC activity, uncovering an unanticipated role of this enzyme in the late structuring and function of neuronal networks. [Copyright &y& Elsevier]

The mesencephalic dopaminergic (mesDA) system controls movement and emotional behaviour, and its degeneration causes Parkinson''s disease and other psychiatric disorders. Recent findings are leading to better understanding of the genetic control of generation and functioning of the mesDA system. This advancement could disclose new perspectives for therapeutic approaches of mesDA-related disorders. [Copyright &y& Elsevier]

Otx1 and Otx2, the murine homologs of the Drosophila orthodenticle gene, play a remarkable role in specification and regionalization of forebrain and midbrain. Recently, genetic approaches have indicated that OTD, OTX1 and OTX2 have retained reciprocal functional equivalence in evolution, whereas their regulatory control has been remarkably modified. This suggests that during the evolution of the vertebrate brain, regulatory changes modulating the transcriptional and translational control of pre-existing gene functions might have favored the establishment of new morphogenetic pathways. [Copyright &y& Elsevier]

Focuses on the role of murine homologs of the orthodenticle gene of Drosophilia, Otx1 and Otx2, in brain morphogenesis. Functional redundancy and specificity between Otx1 and Otx2; Role of Otx1 for corticogensis and sense-organ development; Role of Otx2 for specification and maintenance of anterior neural plate and gastrulation.

Discusses the mechanisms responsible for the development of the central nervous system. Function of neuroectoderm; Ambiguity in regionally restricted gene expression; Role of the genes Emx2 and Otx2 in the development of diencephalon; Effects of the interaction between the genes on brain development.

Abstract: Genetic and embryological experiments demonstrated that the visceral endoderm (VE) is essential for positioning the primitive streak at one pole of the embryo and head morphogenesis through antagonism of the Wnt and Nodal signaling pathways. The transcription factor Otx2 is required for VE anteriorization and specification of rostral neuroectoderm at least in part by controlling the expression of Dkk1 and Lefty1. Here, we investigated the relevance of the Otx2 transcriptional control in these processes. Otx2 protein is encoded by different mRNAs variants, which, on the basis of their transcription start site, may be distinguished in distal and proximal. Distal isoforms are prevalently expressed in the epiblast and neuroectoderm, while proximal isoforms prevalently in the VE. Selective inactivation of Otx2 variants reveals that distal isoforms are not required for gastrulation, but essential for maintenance of forebrain and midbrain identities; conversely, proximal isoforms control VE anteriorization and, indirectly, primitive streak positioning through the activation of Dkk1 and Lefty1. Moreover, in these mutants the expression of proximal isoforms is not affected by the lack of distal mRNAs and vice versa. Taken together these findings indicate that proximal and distal isoforms, whose expression is independently regulated in the VE and epiblast-derived neuroectoderm, functionally cooperate to provide these tissues with the sufficient level of Otx2 necessary to promote a normal development. Furthermore, we discovered that in the VE the expression of Otx2 isoforms is tightly controlled at single cell level, and we hypothesize that this molecular diversity may potentially confer specific functional properties to different subsets of VE cells. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

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 &y& Elsevier]