Evolutionary conservation of otd/Otx2 transcription factor action: a genome-wide microarray analysis in Drosophila

BACKGROUND: Homeobox genes of the orthodenticle (otd)/Otx family have conserved roles in the embryogenesis of head and brain. Gene replacement experiments show that the Drosophila otd gene and orthologous mammalian Otx genes are functionally equivalent, in that overexpression of either gene in null mutants of Drosophila or mouse can restore defects in cephalic and brain development. This suggests that otd and Otx genes control a comparable subset of downstream target genes in either organism. Here we use quantitative transcript imaging to analyze this equivalence of otd and Otx gene action at a genomic level. RESULTS: Oligonucleotide arrays representing 13,400 annotated Drosophila genes were used to study differential gene expression in flies in which either the Drosophila otd gene or the human Otx2 gene was overexpressed. Two hundred and eighty-seven identified transcripts showed highly significant changes in expression levels in response to otd overexpression, and 682 identified transcripts showed highly significant changes in expression levels in response to Otx2 overexpression. Among these, 93 showed differential expression changes following overexpression of either otd or Otx2, and for 90 of these, comparable changes were observed under both experimental conditions. We postulate that these transcripts are common downstream targets of the fly otd gene and the human Otx2 gene in Drosophila. CONCLUSION: Our experiments indicate that approximately one third of the otd-regulated transcripts also respond to overexpression of the human Otx2 gene in Drosophila. These common otd/Otx2 downstream genes are likely to represent the molecular basis of the functional equivalence of otd and Otx2 gene action in Drosophila

Unsuspected role of the brain morphogenetic gene Otx1 in hematopoiesis

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-/- mice. Taken together, our findings indicate a function for Otx1 in the regulation of blood cell production. There is growing evidence suggesting that common cellular and molecular mechanisms orchestrate differentiation in various tissues. Homeobox-containing genes seem to be strong candidate genes to regulate a number of developmental processes, including neurogenesis and hematopoiesis. Members of the Otx family (Otx1, Otx2, Otx3, and Crx) are the vertebrate homologues of the Drosophila head gap gene orthodenticle and encode transcription factors containing a bicoid-like homeodomain. They are temporally and spatially regulated during development and seem to be required for proper head and sense organ patterning. Otx1, Otx2, and Otx3 show partially overlapping, but distinct expression patterns, and Otx2, the first to be activated during development, plays a major role in gastrulation and in the early specification of the anterior neural plate. In contrast, Otx1 shows a later onset and is involved in corticogenesis, sense organ development, and pituitary function. Mice bearing targeted deletion of Otx1 are affected by a permanent epileptic phenotype and show multiple brain abnormalities and morphological defects of the acoustic and visual sense organs. In addition, at the prepubescent stage, they exhibit transient dwarfism and hypogonadism because of low levels of pituitary hormones. In the present study, we have investigated whether Otx1 also plays a role in blood cell production, as several homeobox genes of different families are involved in normal and/or malignant hematopoiesis

Mutant p63 causes defective expansion of ectodermal progenitor cells and impaired FGF signalling in AEC syndrome

Peer reviewe

Patterning of the mammalian cochlea

The mammalian cochlea is sophisticated in its function and highly organized in its structure. Although the anatomy of this sense organ has been well documented, the molecular mechanisms underlying its development have remained elusive. Information generated from mutant and knockout mice in recent years has increased our understanding of cochlear development and physiology. This article discusses factors important for the development of the inner ear and summarizes cochlear phenotypes of mutant and knockout mice, particularly Otx and Otx2. We also present data on gross development of the mouse cochlea

The vascular effects of L-arginine in humans: the role of endogenous insulin

This study aimed at evaluating whether increased availability of the natural precursor of nitric oxide, L-arginine, could influence systemic hemodynamic and rheologic parameters in humans and whether the effects of L-arginine are mediated by endogenous insulin. 10 healthy young subjects participated in the following studies: study I, infusion of L-arginine (1 g/min for 30 min); study II, infusion of L-arginine plus octreotide (25 �g as i.v. bolus � 0.5 �g/min) to block endogenous insulin and glucagon secretion, plus replacement of basal insulin and glucagon; study III, infusion of L-arginine plus octreotide plus basal glucagon plus an insulin infusion designed to mimic the insulin response of study I. L-Arginine infusion significantly reduced systolic (11�3, mean�SE) and diastolic (8�2 mmHg, P � 0.001) blood pressure, platelet aggregation (20�4%), and blood viscosity (1.6�0.2 centipois, P � 0.01), and increased leg blood flow (97�16 ml/min), heart rate, and plasma catecholamine levels (P � 0.01). In study II, plasma insulin levels remained suppressed at baseline; in this condition, the vascular responses to L-arginine were significantly reduced, except for plasma catecholamines which did not change significantly. In study III, the plasma insulin response to L-arginine was reestablished; this was associated with hemodynamic and rheologic changes following L-arginine not significantly different from those recorded in study I. These findings show that systemic infusion of L-arginine in healthy subjects induces vasodilation and inhibits platelet aggregation and blood viscosity. These effects are mediated, in part, by endogenou