Transcription factors of the forkhead box, class O (FoxO) family are important regulators of the cellular stress response and promote the cellular antioxidant defense. On one hand, FoxOs stimulate the transcription of genes coding for antioxidant proteins located in different subcellular compartments, such as in mitochondria (i.e. superoxide dismutase-2, peroxiredoxins 3 and 5) and peroxisomes (catalase), as well as for antioxidant proteins found extracellularly in plasma (e.g., selenoprotein P and ceruloplasmin). On the other hand, reactive oxygen species (ROS) as well as other stressful stimuli that elicit the formation of ROS, may modulate FoxO activity at multiple levels, including posttranslational modifications of FoxOs (such as phosphorylation and acetylation), interaction with coregulators, alterations in FoxO subcellular localization, protein synthesis and stability. Moreover, transcriptional and posttranscriptional control of the expression of genes coding for FoxOs is sensitive to ROS. Here, we review these aspects of FoxO biology focusing on redox regulation of FoxO signaling, and with emphasis on the interplay between ROS and FoxOs under various physiological and pathophysiological conditions. Of particular interest are the dual role played by FoxOs in cancer development and their key role in whole body nutrient homeostasis, modulating metabolic adaptations and/or disturbances in response to low vs. high nutrient intake. Examples discussed here include calorie restriction and starvation as well as adipogenesis, obesity and type 2 diabetes.
BSAP has been identified previously as a transcription factor that is expressed at early, but not late, stages of B-cell differentiation. Biochemical purification and cDNA cloning has now revealed that BSAP belongs to the family of paired domain proteins. BSAP is encoded by the Pax-5 gene and has been highly conserved between human and mouse. An intact paired domain was shown to be both necessary and sufficient for DNA binding of BSAP. Binding studies with several BSAP recognition sequences demonstrated that the sequence specificity of BSAP differs from that of the distantly related paired domain protein Pax-1. During embryogenesis, the BSAP gene is transiently expressed in the mesencephalon and spinal cord with a spatial and temporal expression pattern that is distinct from that of other Pax genes in the developing central nervous system (CNS). Later, the expression of the BSAP gene shifts to the fetal liver where it correlates with the onset of B lymphopoiesis. BSAP expression persists in B lymphocytes and is also seen in the testis of the adult mouse. All of this evidence indicates that the transcription factor BSAP may not only play an important role in B-cell differentiation but also in neural development and spermatogenesis.
In the human paired box-containing (PAX) gene family, only two members, PAX-3 and PAX-6, which are associated with Waardenburg's syndrome and aniridia, respectively have been mapped to human chromosomes. We have now isolated cosmids for six additional human PAX genes (PAX-1,-2,-5,-7,-8,-9) and a polymerase chain reaction fragment for PAX-4. PAX-9 is a novel family member which is closely related in its paired domain to PAX-1. The chromosomal location of all cloned PAX genes was determined by analysis of somatic cell hybrids and (except PAX-4) by fluorescence in situ hybridization to metaphase chromosomes. PAX-1 and PAX-7 map to chromosomal regions containing previously assigned disease loci.
Embryonic stem (ES) cells provide a unique tool for producing specifically designed mutations in mice. Here, we describe an alternative approach toward the generation of mice which are derived completely from ES cells (ES mice), as judged by glucose phosphate isomerase (GPI) analysis, without prior passage through the germline. By injecting wild-type and mutant ES cells into tetraploid blastocysts, viable and fertile ES mice were generated, suggesting that totipotency of ES cells was not affected by long-term culture and experimental manipulation in vitro. When ES cell clones harboring a lacZ reporter gene introduced by either targeted insertion or a gene-trap approach were used, the expression pattern of the lacZ gene in ES fetuses was identical to that of fetuses that were derived from breeding of chimeric mice. Thus, this technique can be considered as a useful and rapid approach to produce fetuses and mice directly from ES cells carrying predetermined genetic changes and offers many applications for studies in molecular genetics and developmental biology.
Midbrain and cerebellum development depends on an organizing center that is located at the midbrainhindbrain junction of the vertebrate embryo. Expression of the two closely related transcription factors Pax2 and Pax5 overlaps spatially and temporally in this region of the developing central nervous system. To study a possible interaction of these transcription factors in midbrain and cerebellum patterning, we have generated Pax5, Krd double mutant mice. The transgene-induced Krd mutation corresponds to an Ϸ7-centimorgan chromosome 19 deletion that eliminates the entire Pax2 locus. The heterozygous Krd mutation deleting one Pax2 allele had no effect on midbrain and cerebellum development. Moreover, only minor developmental defects were previously observed at the midline of the inferior colliculus and anterior cerebellum in mice that were homozygous for a targeted Pax5 mutation. Similar morphological alterations were observed in 80% of all compound heterozygous Pax5 (؉͞؊) Krd (؉͞؊) mice. However, in the remaining 20% of compound heterozygotes, the inferior colliculi were missing, and the vermis of the cerebellum was severely disrupted due to the failure of the cerebellar primordia to fuse at the midline. Inactivation of the second Pax5 allele in Pax5 (؊͞؊) Krd (؉͞؊) mice resulted in complete loss of the posterior midbrain and cerebellum, as the tissue originating from the midbrain-hindbrain boundary region was deleted in the embryo as early as day 9.5. On the basis of these data, we propose that the cooperation of Pax2 and Pax5 is essential for normal functioning of the organizing center at the midbrainhindbrain junction.
The development of two major subdivisions of the vertebrate nervous system, the midbrain and the cerebellum, is controlled by signals emanating from a constriction in the neural primordium called the midbrain͞ hindbrain organizer ( The neural tube is regionalized by successive division of the neuroepithelium into distinct areas of the central nervous system. The boundaries between these regions can be recognized by the region-specific expression of certain genes as well as by morphological landmarks like constrictions in the neural tube (1). The earliest four subdivisions of the developing neural tube are the forebrain, the midbrain, the hindbrain, and the spinal cord. The boundary between midbrain and hindbrain is of particular interest because it has been shown to control the development of the mesencephalon and metencephalon (reviewed in ref.2). A number of regulatory proteins are known to play an important role in the establishment and the maintenance of the midbrain͞hindbrain organizer, among them the two secreted molecules Wnt-1 and FGF-8, the homeodomain containing transcription factors En-1 and En-2, and the paired domain-containing transcription factors Pax-2 and reviewed in ref. 10). Pax-2 is the earliest of these genes expressed in the prospective midbrain͞ hindbrain boundary, and its expression precedes the abovementioned genes (11). The functions of all these molecules have been studied in mice (3, 4, 6-9, 12, 13) by means of targeted or naturally occurring mutations. The phenotypes described for these mutations include either abnormalities in the development of the structures derived from the organizing center (En-2 and Pax-5) or variable deletions of midbrain and cerebellum tissue around the mesencephalon͞metencephalon constriction (Wnt-1 and En-1). It has been demonstrated that the weak brain phenotype of the En-2 null mutation is caused by functional redundancy of a second member of this gene family, En-1, which is overlappingly expressed (14). A similar mechanism of functional substitution in this region has been suggested to explain the weak brain phenotype of Pax-5 (3) because of redundant function of the closely related Pax-2 gene.Furthermore, cooperation of Pax-2 and Pax-5 in midbrain and cerebellum development has been suggested on the basis of the phenotype of mice carrying both the Pax-5 and Krd mutations (15). The Krd mutation results from a mostly uncharacterized 7-cM deletion in chromosome 19, which comprises among other alterations the deletion of the whole Pax-2 locus (16). The homozygous Krd mutation is lethal at the preimplantation stage. The compound Pax-5 homozygous and Krd heterozygous mutant mice show a complete loss of the posterior midbrain and cerebellum (15), which is similar to the phenotype of the En-1 mutant mice (13).In the present study we analyze the midbrain͞hindbrain phenotype of mice carrying a targeted deletion of Pax-2 (back-crossed into C57BL͞6) and discover that it has no obvious morphological alterations in the brainstem, suggesting a possible redund...
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