In mammals, insulin signalling regulates glucose transport together with the expression and activity of various metabolic enzymes. In the nematode Caenorhabditis elegans, a related pathway regulates metabolism, development and longevity. Wild-type animals enter the developmentally arrested dauer stage in response to high levels of a secreted pheromone, accumulating large amounts of fat in their intestines and hypodermis. Mutants in DAF-2 (a homologue of the mammalian insulin receptor) and AGE-1 (a homologue of the catalytic subunit of mammalian phosphatidylinositol 3-OH kinase) arrest development at the dauer stage. Moreover, animals bearing weak or temperature-sensitive mutations in daf-2 and age-1 can develop reproductively, but nevertheless show increased energy storage and longevity. Here we show that null mutations in daf-16 suppress the effects of mutations in daf-2 or age-1; lack of daf-16 bypasses the need for this insulin receptor-like signalling pathway. The principal role of DAF-2/AGE-1 signalling is thus to antagonize DAF-16. daf-16 is widely expressed and encodes three members of the Fork head family of transcription factors. The DAF-2 pathway acts synergistically with the pathway activated by a nematode TGF-beta-type signal, DAF-7, suggesting that DAF-16 cooperates with nematode SMAD proteins in regulating the transcription of key metabolic and developmental control genes. The probable human orthologues of DAF-16, FKHR and AFX, may also act downstream of insulin signalling and cooperate with TGF-beta effectors in mediating metabolic regulation. These genes may be dysregulated in diabetes.
The establishment of the cardiovascular system represents an early, critical event essential for normal embryonic development, and defects in cardiovascular development are a frequent cause of both in utero and neonatal demise. Congenital cardio-vascular malformations, the most frequent birth defect, can occur as isolated events, but are frequently presented clinically within the context of a constellation of defects that involve multiple organs and that define a specific syndrome. In addition, defects can be a primary effect of gene mutations or result from secondary effects of altered cardiac physiology. Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the heart, liver, eye, skeleton and kidney. Congenital heart defects, the majority of which affect the right-sided or pulmonary circulation, contribute significantly to mortality in AGS patients. Recently, mutations in Jagged1 ( JAG1 ), a conserved gene of the Notch intercellular signaling pathway, have been found to cause AGS. In order to begin to delineate the role of JAG1 in normal heart development we have studied the expression pattern of JAG1 in both the murine and human embryonic heart and vascular system. Here, we demonstrate that JAG1 is expressed in the developing heart and multiple associated vascular structures in a pattern that correlates with the congenital cardiovascular defects observed in AGS. These data are consistent with an important role for JAG1 and Notch signaling in early mammalian cardiac development.
Under conditions of high population density and low food, Caenorhabditis elegans forms an alternative third larval stage, called the dauer stage, which is resistant to desiccation and harsh environments. Genetic analysis of some dauer constitutive (Daf-c) and dauer defective (Daf-d) mutants has revealed a complex pathway that is likely to function in particular neurons and/or responding tissues. Here we analyze the genetic interactions between three genes which comprise a branch of the dauer formation pathway that acts in parallel to or downstream of the other branches of the pathway, the Daf-c genes daf-2 and daf-23 and the Daf-d gene daf-16. Unlike mutations in other Daf-c genes, mutations in both daf-2 and daf-23 cause non-conditional arrest at the dauer stage. Our epistasis analysis suggests that daf-2 and daf-23 are functioning at a similar point in the dauer pathway. First, mutations in daf-2 and daf-23 are epistatic to mutations in the same set of Daf-d genes. Second, daf-2 and daf-23 mutants are suppressed by mutations in daf-16. Mutations in daf-16 do not suppress any of the other Daf-c mutants as efficiently as they suppress daf-2 and daf-23 mutants. Third, double mutants between either daf-2 or daf-23 and several other daf-d mutants exhibit an unusual interaction. Based on these results, we present a model for the function of daf-2, daf-23 and daf-16 in dauer formation.
This study shows that RADSO, a yeast DNA repair gene required for meiotic interchromosomal exchange between homologs, also is required for meiotic intrachromosomal recombination. However, only intrachromosomal events in nonribosomal DNA are dependent on RAD5O; those in ribosomal DNA (rRNA-encoding DNA) occur in the absence of this gene. Furthermore, nonribosomal DNA sequences retain theirRADSO-dependence even when inserted into the ribosomal DNA array. We argue that these data provide evidence for at least two pathways of meiotic intrachromosomal recombination whose activity depends on the specific sequences involved or their structural context in the chromosome. In contrast to its role in meiosis, RAD5O is not required for either inter-or intrachromosomal spontaneous mitotic recombination.Genetic exchange functions in several important ways in eukaryotic cells. In addition to contributing to genetic diversity during gametogenesis, it also is required for proper distribution of homologs at meiosis I (1, 2), maintenance of copy number (3)(4)(5) and sequence homogeneity (6-8) in repeated gene families, creation of new alleles (9, 10), and control ofgene expression (11)(12)(13). Despite the importance of these various recombination (Rec) events, relatively little is known at present about eukaryotic recombination genes particularly in higher organisms.In this study we used the yeast Saccharomyces cerevisiae as a model system to examine the mechanism of intrachromosomal recombination. Using a process of single-division meiosis in haploid and diploid cells that eliminates meiosis I segregation of homologs (2,14), we have inquired whether intrachromosomal recombination and interchromosomal recombination utilize the same recombination functions and occur via a common recombination gene pathway(s).In this system it was previously shown that (i) interchromosomal reciprocal exchange occurs at similar levels to standard two-division meiosis (14, 15); (ii) genetic map distances along the length of chromosome III are the same in recombination-proficient (Rec+) diploids (2n) and disomic haploids (n + 1)-i.e., the presence or absence of pairing and exchange on other homologs does not affect recombination on this chromosome (15); (iii) intrachromosomal events between duplicated genes are elevated in the absence ofa paired homolog (16); and (iv) the SPOil gene encodes a recombination function required in common for exchange between and within individual chromosomes (16).Here we report that a second gene, RAD50, also is used in common; however, RAD50, unlike SPOIl, is not essential for all intrachromosomal recombination. Based on this evidence we propose that there are at least two partially overlapping pathways of intrachromosomal exchange acting on different sequences in the genome. Recombination functions in both of these pathways are shared with those that operate in interchromosomal exchange.
MATERIALS AND METHODSMedia and Genetic Procedures. Growth and sporulation media are as described (17). The radSO-J mutation, w...
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