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At least 703 records · Page 39Linked to original sources
PubMed2002

A serpin mutant links Toll activation to melanization in the host defence of Drosophila.

A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component.

Animals↗
PubMed2003

The magnitude of hedgehog signaling activity defines skin tumor phenotype.

Gain-of-function mutations in SMO have been implicated in constitutive activation of the hedgehog signaling pathway in human basal cell carcinomas (BCCs). We used a truncated keratin 5 (DeltaK5) promoter to assess the potential role of the human M2SMO mutant in BCC development in adult transgenic mice. DeltaK5-M2SMO mouse epidermis is hyperproliferative, ex presses BCC protein markers and gives rise to numerous epithelial downgrowths invading the underlying dermis. Lesions strikingly similar to human basaloid follicular hamartomas develop, but BCCs do not arise even in elderly mice. Hedgehog target gene transcripts were only modestly upregulated in mouse and human follicular hamartomas, in contrast to the high levels detected in BCCs. Cyclins D1 and D2 were selectively upregulated in mouse BCCs. Our data suggest that the levels of hedgehog pathway activation and G(1) cyclins are major determinants of tumor phenotype in skin, and strongly implicate deregulated hedgehog signaling in the genesis of human basaloid follicular hamartomas. Expression of an activated SMO mutant in keratinocytes appears to be insufficient for the development and/or maintenance of full-blown BCCs.

Alopecia↗
PubMed1988

The antimorphic nature of the Tc allele at the mouse T locus.

The T locus on mouse chromosome 17 is haploid-insufficient: deletion/+ heterozygous mice have a short tail. One exceptional allele, Tc, produces a tailless phenotype in heterozygous mice. Thus, Tc has a more severe phenotype than that of a deletion allele, suggesting either that Tc is further deleted for a neighboring locus, resulting in the additional phenotype, or that Tc is a gain-of-function mutation. We have shown that Tc is not deleted for the D17Leh119 and D17RP17 loci flanking T, which are deleted in some T alleles. Thus, the severity of the Tc phenotype is not due to the deletion of an adjacent locus. We have also examined the genetic nature of the Tc allele by placing it in trans with a T-locus duplication, twLub2, which has previously been independently confirmed at the molecular level to have a duplication in the chromosomal region including the T locus. We have shown that Tc is partially complemented by twLub2, unlike a null allele (deletion) which was previously shown to be fully complemented by twLub2. These results indicate that Tc behaves genetically as an antimorph, exerting its effect by antagonizing the function of a wild-type allele at the T locus. The apparent correlation between the gene dosage at the T locus and the length of the body axis is discussed.

Alleles↗
PubMed1992

Genetic analysis of the additional sex combs locus of Drosophila melanogaster.

Additional sex combs (Asx) is a member of the Polycomb group of genes, which are thought to be required for maintenance of chromatin structure. To better understand the function of Asx, we have isolated nine new alleles, each of which acts like a gain of function mutation. Asx is required for normal determination of segment identity. AsxP1 shows an unusual phenotype in that anterior and posterior homeotic transformations are seen in the same individuals, suggesting that AsxP1 might upset chromatin structure in a way that makes both activation and repression of homeotic genes more difficult. Analysis of embryonic and adult phenotypes of Asx alleles suggests that Asx is required zygotically for determination of segment number and polarity. The expression pattern of even-skipped is altered in Asx mutant embryos, suggesting that Asx is required for normal expression of this gene. We have transposon-tagged the Asx gene, and can thus begin molecular analysis of its function.

Alleles↗
PubMed1998

Transvection in the Drosophila Abd-B domain: extensive upstream sequences are involved in anchoring distant cis-regulatory regions to the promoter.

The Abd-B gene, one of the three homeotic genes in the Drosophila bithorax complex (BX-C), is required for the proper identity of the fifth through the eighth abdominal segments (corresponding to parasegments 10-14) of the fruitfly. The morphological difference between these four segments is due to the differential expression of Abd-B, which is achieved by the action of the parasegment-specific cis-regulatory regions infra-abdominal-5 (iab-5), -6, -7 and -8. The dominant gain-of-function mutation Frontabdominal-7 (Fab-7) removes a boundary separating two of these cis-regulatory regions, iab-6 and iab-7. As a consequence of the Fab-7 deletion, the parasegment 12- (PS12-) specific iab-7 is ectopically activated in PS11. This results in the transformation of the sixth abdominal segment (A6) into the seventh (A7) in Fab-7 flies. Here we report that point mutations of the Abd-B gene in trans suppress the Fab-7 phenotype in a pairing-dependent manner and thus represent a type of transvection. We show that the observed suppression is the result of trans-regulation of the defective Abd-B gene by the ectopically activated iab-7. Unlike previously demonstrated cases of trans-regulation in the Abd-B locus, trans-suppression of Fab-7 is sensitive to heterozygosity for chromosomal rearrangements that disturb homologous pairing at the nearby Ubx locus. However, in contrast to Ubx, the transvection we observed in the Abd-B locus is insensitive to the allelic status of zeste. Analysis of different deletion alleles of Abd-B that enhance trans-regulation suggests that an extensive upstream region, different from the sequences required for transcription initiation, mediates interactions between the iab cis-regulatory regions and the proximal Abd-B promoter. Moreover, we find that the amount of DNA deleted in the upstream region is roughly proportional to the strength of trans-interaction, suggesting that this region consists of numerous discrete elements that cooperate in tethering the iab regulatory domains to Abd-B. Possible implications of the tethering complex for the regulation of Abd-B are discussed. In addition, we present evidence that the tenacity of trans-interactions in the Abd-B gene may vary, depending upon the tissue and stage of development.

Abdomen↗
PubMed2000

Calcium/calmodulin-dependent protein kinase II regulates Caenorhabditis elegans locomotion in concert with a G(o)/G(q) signaling network.

Caenorhabditis elegans locomotion is a complex behavior generated by a defined set of motor neurons and interneurons. Genetic analysis shows that UNC-43, the C. elegans Ca(2+)/calmodulin protein kinase II (CaMKII), controls locomotion rate. Elevated UNC-43 activity, from a gain-of-function mutation, causes severely lethargic locomotion, presumably by inappropriate phosphorylation of targets. In a genetic screen for suppressors of this phenotype, we identified multiple alleles of four genes in a G(o)/G(q) G-protein signaling network, which has been shown to regulate synaptic activity via diacylglycerol. Mutations in goa-1, dgk-1, eat-16, or eat-11 strongly or completely suppressed unc-43(gf) lethargy, but affected other mutants with reduced locomotion only weakly. We conclude that CaMKII and G(o)/G(q) pathways act in concert to regulate synaptic activity, perhaps through a direct interaction between CaMKII and G(o).

Animals↗
PubMed2001

Drosophila-raf acts to elaborate dorsoventral pattern in the ectoderm of developing embryos.

In the early Drosophila embryo the activity of the EGF-receptor (Egfr) is required to instruct cells to adopt a ventral neuroectodermal fate. Using a gain-of-function mutation we showed that D-raf acts to transmit this and other late-acting embryonic Egfr signals. A novel role for D-raf was also identified in lateral cell development using partial loss-of-function D-raf mutations. Thus, we provide evidence that zygotic D-raf acts to specify cell fates in two distinct pathways that generate dorsoventral pattern within the ectoderm. These functional requirements for D-raf activity occur subsequent to its maternal role in organizing the anterioposterior axis. The consequences of eliminating key D-raf regulatory domains and specific serine residues in the transmission of Egfr and lateral epidermal signals were also addressed here.

Animals↗
PubMed2003

Drosophila gain-of-function mutant RTK torso triggers ectopic Dpp and STAT signaling.

Overactivation of receptor tyrosine kinases (RTKs) has been linked to tumorigenesis. To understand how a hyperactivated RTK functions differently from wild-type RTK, we conducted a genome-wide systematic survey for genes that are required for signaling by a gain-of-function mutant Drosophila RTK Torso (Tor). We screened chromosomal deficiencies for suppression of a gain-of-function mutation tor (tor(GOF)), which led to the identification of 26 genomic regions that, when in half dosage, suppressed the defects caused by tor(GOF). Testing of candidate genes in these regions revealed many genes known to be involved in Tor signaling (such as those encoding the Ras-MAPK cassette, adaptor and structural molecules of RTK signaling, and downstream target genes of Tor), confirming the specificity of this genetic screen. Importantly, this screen also identified components of the TGFbeta (Dpp) and JAK/STAT pathways as being required for Tor(GOF) signaling. Specifically, we found that reducing the dosage of thickveins (tkv), Mothers against dpp (Mad), or STAT92E (aka marelle), respectively, suppressed tor(GOF) phenotypes. Furthermore, we demonstrate that in tor(GOF) embryos, dpp is ectopically expressed and thus may contribute to the patterning defects. These results demonstrate an essential requirement of noncanonical signaling pathways for a persistently activated RTK to cause pathological defects in an organism.

Animals↗
PubMed2001

Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility.

The 'paired'-like homeodomain transcription factor Prop1 is essential for the expansion of the pituitary primordia and for the differentiation and/or function of the hormone-producing cells of the anterior pituitary gland. Prop1 expression is normally extinguished before transcription of most differentiation markers is initiated. We report that constitutive expression of Prop1 interferes with anterior pituitary cell differentiation and increases the susceptibility for pituitary tumors. The terminal differentiation of pituitary gonadotropes is delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurs normally, but thyrotrope function is impaired resulting in mild hypothyroidism. Aged mice exhibit defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke's cleft cysts and tumors. Thus, silencing Prop1 is important for normal pituitary development and function. These data suggest that gain-of-function mutations in PROP1 could contribute to the most common human pituitary endocrinopathies and tumors.

Adenoma↗
PubMed2002

A mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease, caused by the expansion of a trinucleotide repeat (TNR) in exon 1 of the androgen receptor (AR) gene. This disorder is characterized by degeneration of motor and sensory neurons, proximal muscular atrophy, and endocrine abnormalities, such as gynecomastia and reduced fertility. We describe the development of a transgenic model of SBMA expressing a full-length human AR (hAR) cDNA carrying 65 (AR(65)) or 120 CAG repeats (AR(120)), with widespread expression driven by the cytomegalovirus promoter. Mice carrying the AR(120) transgene displayed behavioral and motor dysfunction, while mice carrying 65 CAG repeats showed a mild phenotype. Progressive muscle weakness and atrophy was observed in AR(120) mice and was associated with the loss of alpha-motor neurons in the spinal cord. There was no evidence of neurodegeneration in other brain structures. Motor dysfunction was observed in both male and female animals, showing that in SBMA the polyglutamine repeat expansion causes a dominant gain-of-function mutation in the AR. The male mice displayed a progressive reduction in sperm production consistent with testis defects reported in human patients. These mice represent the first model to reproduce the key features of SBMA, making them a useful resource for characterizing disease progression, and for testing therapeutic strategies for both polyglutamine and motor neuron diseases.

Animals↗
PubMed2003

Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy.

Huntington's disease is caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. This gain-of-function mutation is associated with huntingtin aggregation and cell death. Autophagy is an important clearance route for mutant huntingtin exon 1. While mammalian target of rapamycin (mTOR) is a key regulator of autophagy, the upstream modifiers of this process are poorly understood. Our previous expression profiling studies in HD cell models observed changes in four genes associated with glucose metabolism, including the GLUT1 glucose transporter. A role for intracellular glucose as a modulator for polyglutamine toxicity was suggested as cell death was reduced by GLUT1 overexpression. Here we show that the protective effect of GLUT1 is associated with decreased huntingtin exon 1 aggregation in cell models. Consistent with this result, we also observed reduced aggregation and enhanced clearance of mutant huntingtin when cells were cultured in raised glucose concentrations (8 g/l). These effects were mimicked by 8 g/l 2-deoxyglucose (2DOG) (transported, phosphorylated but not metabolized further), but not with 8 g/l 3-O-methyl glucose (transported but not metabolized further). Thus, this phenomenon is probably mediated by glucose-6-phosphate. Increased clearance of mutant huntingtin by raised glucose (8 g/l) and 2DOG correlated with increased autophagy and reduced phosphorylation of mTOR, S6K1 and Akt. Thus, raised intracellular glucose/glucose 6-phosphate levels reduce mutant huntingtin toxicity by increasing autophagy via mTOR and possibly Akt. As mTOR and Akt regulate a diversity of crucial cellular processes, our data also suggest a major new set of targets for intracellular glucose signalling.

Animals↗
PubMed2006

Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis.

Boundaries between cellular compartments often serve as signaling interfaces during embryogenesis. The coronal suture is a major growth center of the skull vault and develops at a boundary between cells derived from neural crest and mesodermal origin, forming the frontal and parietal bones, respectively. Premature fusion of these bones, termed coronal synostosis, is a common human developmental anomaly. Known causes of coronal synostosis include haploinsufficiency of TWIST1 and a gain of function mutation in MSX2. In Twist1(+/-) mice with coronal synostosis, we found that the frontal-parietal boundary is defective. Specifically, neural crest cells invade the undifferentiated mesoderm of the Twist1(+/-) mutant coronal suture. This boundary defect is accompanied by an expansion in Msx2 expression and reduction in ephrin-A4 distribution. Reduced dosage of Msx2 in the Twist1 mutant background restores the expression of ephrin-A4, rescues the suture boundary and inhibits craniosynostosis. Underlining the importance of ephrin-A4, we identified heterozygous mutations in the human orthologue, EFNA4, in three of 81 patients with non-syndromic coronal synostosis. This provides genetic evidence that Twist1, Msx2 and Efna4 function together in boundary formation and the pathogenesis of coronal synostosis.

Animals↗
PubMed2004

TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo.

Factors influencing the development of CD4+CD25+ T-cells in vivo are poorly understood. In order to investigate the contribution of TGFbeta1 to the development and function of CD4+CD25+ T-cells, we generated a gain of function mutation resulting in the overexpression of an active form of TGFbeta1 in T-cells under control of the human CD2 promoter. In peripheral lymphoid organs and in the thymus, the frequency of CD4+CD25+ T-cells was increased in transgenic mice. This appeared to be due to an autocrine effect of TGFbeta on T-cells, since concomitant impairment of TGFbeta-signaling in double transgenic mice resulted in a phenotype similar to wild type. In contrast, in single transgenic mice with impaired TGFbeta-signaling in T-cells, CD4+CD25+ T-cell numbers were reduced in peripheral lymphoid organs but not in the thymus. In addition, TGFbeta was found to regulate the expression of Foxp3 in vivo, a transcription factor essential for the generation and function of regulatory T-cells. In CD4+CD25+ T-cells, TGFbeta1 increased the expression of Foxp3, whereas a decreased expression was seen in CD4+CD25+ T-cells with impaired TGFbeta-signaling. TGFbeta1 induced the expression of IL-10 in transgenic T-cells, but the increased in vitro suppressive capacity observed in transgenic CD4+CD25+ T-cells was due to the secretion of TGFbeta and not IL-10. Therefore, our study provides in vivo evidence for a role of TGFbeta in the homeostasis of CD4+CD25+ T-cells.

Animals↗
PubMed2005

Acquired bartter-like syndrome associated with gentamicin administration.

Although acute nonoliguric renal failure is a well-known nephrotoxic effect of aminoglycoside antibiotics, less recognized is acquired Bartter-like syndrome. Herein, we describe four female patients who presented with marked paresthesia, muscle weakness, and tetany following gentamicin therapy with total dose ranging from 1.2 g to 2.6 g. All were normotensive. Biochemical abnormalities included hypokalemia (K+ 1.8-2.3 mmol/L), metabolic alkalosis (HCO(3-) 31.9-34.2 mmol/L), hypomagnesemia (Mg2+ 0.9-1.2 mg/dL), hypermagnesiuria (fractional excretion of Mg 3-6%), hypocalcemia (free Ca2+ 2.0-4.1 mg/dL), and hypercalciuria (molar ratio of Ca2+/creatinine 0.23-0.53), all consistent with Bartter-like syndrome. Serum immunoreactive parathyroid hormone concentration was low despite the hypocalcemia. The Bartter-like syndrome lasted for 2 to 6 weeks after cessation of gentamicin, coupled with supplementation of K+, Ca2+, and Mg2+. These biochemical abnormalities resembled those seen in patients with gain-of-function mutations in the calcium-sensing receptor. We hypothesize that gentamicin, a polyvalent cationic molecule, induces the action of calcium-sensing receptor on the thick ascending loop of Henle and distal convoluted tubule to cause renal wasting of Na+, K+, Cl-, Ca2+, and Mg2+.

Adult↗
PubMed2001

Gastrointestinal autonomic nerve tumor: immunohistochemical and molecular identity with gastrointestinal stromal tumor.

Gastrointestinal autonomic nerve tumor (GANT) is a gastrointestinal neoplasm that ultrastructurally recapitulates the enteric neural plexus. This study identifies and defines the features of 10 cases of this rare mesenchymal tumor and compares its clinicopathologic and molecular genetic features with the data on gastrointestinal stromal tumor (GIST). The majority of patients in this series presented at an older age (mean 64 years). Tumors arose from the stomach (6), small intestine (2), and retroperitoneum (2). Mean tumor size was 14 cm; however, four neoplasms were <6 cm. Histologically, tumors were spindled or epithelioid; one epithelioid tumor demonstrated a previously undescribed rhabdoid histologic phenotype. All tumors were positive for CD117 (KIT), while eight of 10 were positive for CD34. In contrast, only two were positive for S-100, and all were negative for actin and desmin. Five GANTs demonstrated GIST-specific gain-of-function mutations in the juxtamembrane domain of the c-kit gene (50%). Three of 10 patients died of disease in 22-30 months, one patient died in the postoperative period, and one patient died of complications of CML. The clinicopathologic, histologic, immunohistologic, and molecular features of GANT are similar to GIST, indicating that GANT merely represents a phenotypic variant of GIST.

Adult↗
PubMed2001

Cytochrome oxidase activity is increased in +/Lc Purkinje cells destined to die.

+/Lc Purkinje cells degenerate postnatally because of a gain-of-function mutation in the delta2 glutamate receptor (Grid2) that causes a constitutive Na+ current leak. The effect of the resulting chronic depolarization on Purkinje cell metabolism was investigated by measuring levels of cytochrome oxidase (COX) activity in Purkinje cell dendrites using quantitative densitometry. Analysis of wild type controls and +/Lc mutants at P10, P15 and P25 showed that levels of COX activity were significantly increased above control levels by P15 and continued to increase through P25. The increase in COX activity is likely to reflect an increase in oxidative phosphorylation to accommodate the energy demands of removing excess Na+ and Ca2+ entering the Purkinje cells in response to the Grid2 leak current.

Aging↗
PubMed2000

Disorders of thyrotropin synthesis, secretion, and function.

Advances related to thyrotropin during 1999 included better understanding of the genetic basis of pituitary development and genetic advances in identifying clinical entities and their mechanisms and enabling new therapies. Initial clinical use of recombinant thyrotropin in evaluation of thyroid cancer recurrence was described. The importance of glycosylation pattern was clarified including the role of thyrotropin-releasing hormone in synthesis of thyrotropin molecules with mature glycosylation, and the impact of abnormal glycosylation in loss-of-function and gain-of-function mutations of the thyrotropin receptor. Causes of excessive thyrotropin secretion were evaluated, including pituitary thyrotropin-secreting adenomas. The fairly common causes of central hypothyroidism including ischemic injury, cranial irradiation, psychiatric conditions, or medical illness were assessed. The action of thyrotropin at the thyroid cell was assessed as a growth factor and as an influence on tyrosine sulfate content of thyroglobulin. Such basic and clinical science advances are rapidly affecting clinical care.

Adenoma↗
PubMed2001

Genetic defects in thyroid hormone synthesis.

Thyroid hormone synthesis requires a normally developed thyroid gland, a properly functioning hypothalamic-pituitary-thyroid axis, and sufficient iodine intake. This article focuses on genetic defects in this axis. Defects that are primarily of developmental origin are discussed in our associated article in this issue. Defects in hormone synthesis usually are associated with the development of a goiter, provided that the bioactivity and action of thyrotropin (TSH) are not impaired. In contrast, hypoplasia of the gland may be caused by developmental defects, bioinactive TSH, or resistance to TSH at the level of the receptor or its signaling pathway. At the other end of the spectrum, hyperthyroidism may result from gain of function mutations in genes regulating growth and function.

Congenital Hypothyroidism↗