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PubMedDate not supplied

Plasminogen activator inhibitor-1 is a downstream mediator of the PGP9.5-related oncogenic pathway in esophageal squamous cell carcinoma.

BACKGROUND & MATERIALS AND METHODS: Recently, it has been proved that PGP9.5 is an oncogene candidate for squamous cell carcinomas. To examine the PGP9.5-related oncogenic pathway, we tested for global patterns of gene expression in cancer cells following PGP9.5 gene introduction using an oligonucleotide microarray approach. RESULTS: Plasminogen activator inhibitor-1 (PAI-1) was identified as an overexpressed gene in a PGP9.5-expressed esophageal squamous cancer cell line. To confirm the data obtained, we performed Northern analysis using a PGP9.5 or a PAI-1 cDNA probe and found that PAI-1 mRNA was induced by PGP9.5 expression in NUEC1 cells. We further examined endogenous PGP9.5 and PAI-1 expression in 6 esophageal cancer cell lines. One cell line (NUEC2) with PGP9.5 expression exhibited PAI-1 expression, suggesting the possibility that PGP9.5 might induce PAI-1 directly or indirectly. CONCLUSION: These results suggested that PAI-1 might be a novel downstream mediator of PGP9.5 in esophageal squamous cell carcinomas.

Adenoviridae↗

PubMed1995

Chondroitin sulfate proteoglycans in the developing cerebral cortex: the distribution of neurocan distinguishes forming afferent and efferent axonal pathways.

The first thalamocortical axons to arrive in the developing cerebral cortex traverse a pathway that is separate from the adjacent intracortical pathway for early efferents, suggesting that different molecular signals guide their growth. We previously demonstrated that the intracortical pathway for thalamic axons is centered on the subplate (Bicknese et al. [1994] J. Neurosci. 14:3500-3510), which is rich in chondroitin sulfate proteoglycans (CSPGs; Sheppard et al. [1991] J. Neurosci. 11:3928-3942), whereas efferent axons cross the subplate to exit in a zone containing much less CSPG. To define the molecular composition of the subplate further, we used antibodies against CSPG core proteins and chondroitin sulfate disaccharides in an immunohistochemical analysis of their distribution in the developing neocortex of the rat. Immunolabeling for neurocan, a central nervous system-specific CSPG (Rauch et al. [1992] J. Biol. Chem. 267:19537-19547), and for chondroitin 6-sulfate and unsulfated chondroitin becomes prominent in the subplate before the arrival of thalamic afferents. Immunolabeling is initially sparse in the cortical plate but appears later in maturing cortical layers. A postnatal decline in immunolabeling occurs uniformly for most proteoglycans, but, in the somatosensory cortex, labeling for neurocan, phosphacan, and chondroitin 4- and 6-sulfate declines in the centers of the whisker barrels before the walls. In contrast to neurocan, immunolabeling for other proteoglycans is either uniformly distributed (syndecan-1, N-syndecan, 5F3, phosphacan, chondroitin 4-sulfate), restricted to axons (PGM1), distributed exclusively on nonneuronal elements (2D6, NG2, and CD44), or undetectable (9.2.27, aggrecan, decorin). Thus, neurocan is a candidate molecule for delineating the intracortical pathway of thalamocortical axons and distinguishing it from that of cortical efferents.

Afferent Pathways↗

PubMed1986

Health risks of PCB spills from electrical equipment.

The Southern California Edison Company (SCE) has instituted a series of control strategies designed to minimize human exposure to polychlorinated biphenyls (PCBs) in electrical equipment used on its system. This paper describes a method of analyzing PCB risks using conservative estimates of human intake of PCBs originating from accidental spills from electrical equipment. The PCB releases from the Edison system were determined. The fate of these releases in soil, air, and water was analyzed to determine how much material reaches human receptors. The air and water pathways were determined to be the most likely candidates for the exposure and risk considerations. PCB intake via ingestion of soil at the spill site was neglected as an exposure pathway. Equipment spills without controls resulted in at the most 2 ng/day human intake of PCBs via the water exposure pathway. This was determined to be negligible in comparison with intake rates used in conjunction with the setting of food tolerance levels based on fish being the main dietary pathway of human exposure. The inhalation exposure of the hundred or so persons in the immediate vicinity of a spill was determined to equal the PCB intakes of the fish-eating subpopulation analyzed by the Food and Drug Administration for 2 ppm tolerance standard in the case of no controls or cleanup. Current cleanup procedures assure that even the persons in the immediate area are well below the intake of the subjects in the fish contamination analysis. All exposures were well below a "virtual safe dose" level estimated in the fish tolerance study.

California↗

PubMed2006

Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia.

We investigated the modulating actions of the nonselective K(+) channel blocker 4-aminopyridine (4-AP) on amyloid beta (Abeta(1-42))-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of Abeta(1-42) (5 mum) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K(+) current (I(K)). Intracellular application of the nonhydrolyzable analog of GTP, GTPgammaS, induced an outward K(+) current with similar properties to the Abeta(1-42)-induced I(K) including sensitivity to 4-AP (IC(50) = 5 mm). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in Abeta(1-42)-treated microglia. Abeta(1-42) peptide also caused a slow, progressive increase in levels of [Ca(2+)](i) (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to Abeta(1-42) led to enhanced p38 mitogen-activated protein kinase and nuclear factor kappaB expression with factors inhibited by 4-AP. Abeta(1-42) also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from Abeta(1-42)-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of Abeta(1-42) into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an Abeta(1-42)-induced I(K) (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology.

4-Aminopyridine↗

PubMed2006

Microarray-based method for monitoring yeast overexpression strains reveals small-molecule targets in TOR pathway.

Identification of the cellular targets of small-molecule hits in phenotypic screens is a central challenge in the development of small molecules as biological tools and potential therapeutics. To facilitate the process of small-molecule target identification, we developed a global, microarray-based method for monitoring the growth of pools of yeast strains, each overexpressing a different protein, in the presence of small molecules. Specifically, the growth of Saccharomyces cerevisiae strains harboring approximately 3,900 different overexpression plasmids was monitored in the presence of rapamycin, which inhibits the target of rapamycin (TOR) proteins. TOR was successfully identified as a candidate rapamycin target, and many additional gene products were implicated in the TOR signaling pathway. We also characterized the mechanism of LY-83583, a small-molecule suppressor of rapamycin-induced growth inhibition. These data enabled functional links to be drawn between groups of genes implicated in the TOR pathway, identified several candidate targets for LY-83583, and suggested a role for mitochondrial respiration in mediating rapamycin sensitivity.

Aminoquinolines↗

PubMed2001

Microtubule depolymerization facilitates contraction of vascular smooth muscle via increased activation of RhoA/Rho-kinase.

The microtubule network is in a dynamic equilibrium between free and polymerized tubulin, with depolymerization resulting in increased cellular contractility (1-4). Originally, microtubule depolymerization was thought to facilitate contractile responses via the release of an internal, mechanical opposition to contraction. However, recent evidence suggests that depolymerization may also lead to the enhanced activity of various intracellular signaling proteins. The precise signaling pathway by which microtubule depolymerization facilitates vascular smooth muscle contraction is unknown. In non-vascular cells, depolymerization initiates stress fiber formation via increased activity of the small G-protein, RhoA (5-7). The role of this signaling candidate in a calcium-sensitizing contractile pathway is well established. We and others have found it tempting to speculate that RhoA mediates a contractile pathway enhanced by microtubule depolymerization. We further hypothesize the involvement of microtubule depolymerization (via RhoA and Rho-kinase) in the regulation of vascular smooth muscle contraction, with evidence of potential augmentations of this pathway contributing to the increased vasoconstrictor sensitivity seen in various hypertensive animal models.

Animals↗

PubMed2005

Biomarkers for melanoma.

PURPOSE OF REVIEW: Given the capricious nature of melanoma, biomarkers that provide significant insight into the behavior of melanoma would greatly aid in identifying patients at risk for disease progression, those whose disease has progressed subclinically, and those who would benefit from currently available systemic therapies. This review focuses on molecular prognostic markers in primary melanoma, markers that aid in the detection of metastatic melanoma, and markers predictive of systemic therapy. RECENT FINDINGS: Significant advances have been made in the field of melanoma biomarkers. Utilization of paraffin-embedded tissue and multiple markers have improved the RT-PCR assays for detection of melanoma cells in lymph node tissue as well as peripheral blood. Lymphangiogenesis has been identified as a novel mechanism for melanoma progression, and candidate markers in the NF-kappaB signaling pathway have been identified to play a key role in melanoma: tumor vasculature interactions. Loss of heterozygosity has been used to identify potential candidates for biochemotherapy. Furthermore, serum S100B protein has been shown to be superior to lactate dehydrogenase in predicting prognosis and response to treatment for patients with advanced melanoma. SUMMARY: Although recent studies have contributed greatly to the development of melanoma markers, it is anticipated that the application of gene expression profiling and proteomics techniques to melanocytic neoplasms will result in the identification of even more effective biomarkers for melanoma than those currently in clinical use.

Biomarkers, Tumor↗

PubMed2004

Probing folding and fluorescence quenching in human gammaD crystallin Greek key domains using triple tryptophan mutant proteins.

Human gammaD crystallin (HgammaD-Crys), a major component of the human eye lens, is a 173-residue, primarily beta-sheet protein, associated with juvenile and mature-onset cataracts. HgammaD-Crys has four tryptophans, with two in each of the homologous Greek key domains, which are conserved throughout the gamma-crystallin family. HgammaD-Crys exhibits native-state fluorescence quenching, despite the absence of ligands or cofactors. The tryptophan absorption and fluorescence quenching may influence the lens response to ultraviolet light or the protection of the retina from ambient ultraviolet damage. To provide fluorescence reporters for each quadrant of the protein, triple mutants, each containing three tryptophan-to-phenylalanine substitutions and one native tryptophan, have been constructed and expressed. Trp 42-only and Trp 130-only exhibited fluorescence quenching between the native and denatured states typical of globular proteins, whereas Trp 68-only and Trp 156-only retained the anomalous quenching pattern of wild-type HgammaD-Crys. The three-dimensional structure of HgammaD-Crys shows Tyr/Tyr/His aromatic cages surrounding Trp 68 and Trp 156 that may be the source of the native-state quenching. During equilibrium refolding/unfolding at 37 degrees C, the tryptophan fluorescence signals indicated that domain I (W42-only and W68-only) unfolded at lower concentrations of GdnHCl than domain II (W130-only and W156-only). Kinetic analysis of both the unfolding and refolding of the triple-mutant tryptophan proteins identified an intermediate along the HgammaD-Crys folding pathway with domain I unfolded and domain II intact. This species is a candidate for the partially folded intermediate in the in vitro aggregation pathway of HgammaD-Crys.

Amino Acid Substitution↗

PubMed1999

Temperature-dependent sex determination in the American alligator: AMH precedes SOX9 expression.

Gonadal morphogenesis is very similar among mammals, birds, and reptiles. Despite this similarity, each group utilises quite different genetic triggers for sex determination. In mammals, testis development is initiated by action of the Y-chromosome gene SRY. Current evidence suggests that SRY may act together with a related gene, SOX9, to activate another gene(s) in the pathway of testicular differentiation. A downstream candidate for regulation by SRY and SOX9 is AMH. In mouse, Sox9 is expressed in the Sertoli cells of the embryonic testis and it precedes the onset of Amh expression. During mouse gonadogenesis, Amh is confined to the embryonic testis, although it later shows postnatal expression in the ovary. Reptiles such as the American alligator, which exhibit temperature-dependent sex determination (TSD) do not have dimorphic sex chromosomes and apparently no SRY orthologue. SOX9 is expressed during testis differentiation in the alligator; however, it appears to be expressed too late to cause testis determination. Here we describe the cloning and expression of the alligator AMH gene and show that AMH expression precedes SOX9 expression during testis differentiation. This is the opposite to that observed in the mouse where SOX9 precedes AMH expression. The data presented here, as well as findings from recent expression studies in the chick, suggest that AMH expression is not regulated by SOX9 in the non-mammalian vertebrates.

Alligators and Crocodiles↗

PubMed2003

Variation in the coding sequence and flanking splice junctions of the estrogen receptor alpha (ERalpha) gene does not play an important role in genetic susceptibility to bipolar disorder or bipolar affective puerperal psychosis.

Genes involved in estrogen pathways have been proposed as possible candidates influencing susceptibility to bipolar disorder and the affective symptoms suffered by many women during the puerperal period. The estrogen receptor alpha (ERalpha) gene in particular has been a subject of interest and has recently been intensively screened for variations of potential relevance to psychiatric disorders, resulting in the identification of four mutations in individuals with bipolar disorder or puerperal psychosis. We have examined the frequency of these four ERalpha variations in a case control study using a group of mixed gender bipolar individuals (N = 231), further classified into subsets of parous bipolar females with (N = 112) and without (N = 50) puerperal psychosis, and a non-psychiatric comparison group (N = 110). We have also investigated the families in which the variations were initially detected, for evidence of co-segregation of the variants with mood disorder. We found no evidence in our case control sample to support the involvement of any of the ERalpha variations in either the aetiology of bipolar disorder or puerperal triggering of bipolar episodes. Nor did we find co-segregation of ERalpha variants and disease in any of the four families examined. We conclude that variation in the coding sequence and flanking splice junctions of the ERalpha gene does not play an important pathogenic role in the majority of cases of Bipolar Disorder or Bipolar Affective Puerperal Psychosis.

Adult↗

PubMed2004

Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus.

BACKGROUND: There is substantial evidence that the risk of spina bifida, a malformation of the caudal neural tube, may be associated with maternal or embryonic disturbances in the folate-homocysteine metabolic axis. Hence, variants of genes that influence this pathway represent an intriguing group of candidate genes for spina bifida and other neural tube defects (NTD). A common variant of the gene for endothelial nitric oxide synthase (NOS3 G894T) was recently added to this group of NTD candidate genes, based on a report demonstrating that homozygosity for the T allele of this variant is associated with increased homocysteine levels in normal adult populations. METHODS: The association between the risk of spina bifida and both the maternal and embryonic genotype for the NOS3 G894T variant was evaluated in data from 301 families by using the transmission disequilibrium test (TDT) and log-linear modeling. RESULTS: Analyses of these data using the TDT provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic NOS3 genotype. However, the log-linear analyses indicated that the risk of spina bifida was significantly associated with the embryonic, but not the maternal, genotype for the NOS3 G894T variant. CONCLUSIONS: The results of the present analyses suggest that the embryonic NOS3 G894T genotype is associated with the risk of spina bifida. Moreover, these analyses highlight the importance of a detailed examination of the study data. Had these analyses been restricted to the methodologically simpler TDT, the association between the NOS3 G894T genotype and risk of spina bifida may well have been overlooked.

Genetic Variation↗

PubMed2002

Candidate tumor suppressor, HCCS-1, is downregulated in human cancers and induces apoptosis in cervical cancer.

To identify the genes involved in cervical carcinogenesis, we applied the mRNA differential display method and identified a candidate tumor suppressor gene, HCCS-1, which was present in normal cervical tissue but absent in cervical cancer, metastatic lymph node and CUMC-6 cervical cancer cell line. HCCS-1 transcripts were expressed in many normal tissues including leukocyte, lung, spleen, liver, heart and uterine cervix. Its expression was absent in 8 human cancer cell lines. HCCS-1-transfected HeLa cells exhibited growth inhibition by about 50%. This inhibitory effect of HCCS-1 on cervical cancer cells was associated with apoptotic process including DNA fragmentation. HCCS-1-transfected HeLa cells were shown to release cytochrome c from mitochondria, which activates caspase-9 and -3 and finally results in cleavage of poly(ADP-ribose) polymerase. Apoptosis formation was detected by propidium-iodide/annexin V. HCCS-1-transfected HeLa cells were more sensitive to adriamycin or UVC ray triggered apoptosis. These results suggest that HCCS-1 is downregulated in multiple human tumor types and may serve as a candidate tumor suppressor gene through apoptotic pathway against human cervical cancer.

Amino Acid Sequence↗

PubMed2005

Modulation of sulfur mustard induced cell death in human epidermal keratinocytes using IL-10 and TNF-alpha.

We compared the effects of overexpressing a tightly regulated anti-inflammatory cytokine, interleukin 10 (IL-10), and the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on sulfur mustard induced cytotoxicity in human epidermal keratinocytes. Both cytokines were overexpressed when compared with the cells transfected with the empty vector as determined by quantitative ELISA. Cells overexpressing interleukin 10 suppressed the pro-inflammatory cytokines interleukin 8 and interleukin 6 following exposure to 50-300 microM sulfur mustard. These cells exhibited delayed onset of sulfur mustard induced cell death. On the other hand, cells overexpressing tumor necrosis factor alpha induced a sustained elevation in both interleukin 6 and 8 expression following exposure to 50-300 microM sulfur mustard. These cells were sensitized to the effects of sulfur mustard that resulted in an increased sulfur mustard induced cell death. Normal human epidermal keratinocytes treated with sulfur mustard exhibited elevated levels of tumor necrosis factor alpha expression and increased activity of nuclear factor kappa B. Gene array data indicated that cells overexpressing interleukin 10 induced several genes that are involved in growth promotion and cell-fate determination. We, therefore, identify IL-10 and TNF-alpha signal transduction pathways and their components as possible candidates for early therapeutic intervention against sulfur mustard induced cell injury.

Autocrine Communication↗

PubMed2004

Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects.

AIMS/HYPOTHESIS: The development of insulin resistance may contribute to the occurrence and progression of the metabolic syndrome associated with obesity. Components contributing to the insulin pathway and its regulation are good candidates for the molecular study of metabolic syndrome pathogenesis. Protein tyrosine phosphatase 1B (PTP 1B) is an important negative regulator of insulin. We investigated whether PTP 1B SNPs are associated with obesity and obesity-related traits as well as global metabolic syndrome in morbidly obese subjects. METHODS: Untranslated and coding regions of the PTP 1B gene were screened in groups of non-diabetic and diabetic obese subjects and in non-obese subjects. Unrelated morbidly obese ( n=711) and non-obese ( n=427) French Caucasian subjects were genotyped for a case-control study. RESULTS: Six SNPs were identified: two rare variants were located in 5'UTR (-109 C>T and -69 C>T), two in the intronic regions (IVS3+38 G>T and IVS5+3666delT) and two have been described previously (P303P in exon 8 and P387L in exon 9). A case-control study showed an association between the frequent IVS5+3666delT SNP and obesity ( p=0.02). In the obese group, associations between PTP 1B SNPs and features of dyslipidaemia were found. P303P was associated with lower apolipoprotein A1 levels ( p=0.05) whereas P387L was associated with higher triglyceride ( p=0.0003), apolipoprotein B ( p=0.09) and lipoprotein a concentrations ( p=0.006). CONCLUSIONS/INTERPRETATION: Our results support the hypothesis that the PTP 1B gene contributes to the polygenic basis of obesity. PTP 1B SNPs may interact with environmental factors to induce more severe phenotypes, e.g. atherogenic dyslipidaemia, in morbidly obese subjects.

Cholesterol↗

PubMed2026

Deficient arsenic methylation and global proteomic reprogramming in human keratinocytes during arsenic-induced skin carcinogenesis.

Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAsIII) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAsIII induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAsIII comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAsIII promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.

Arsenic↗

PubMed2005

Protein-protein interaction and functionTRPC channels.

Since their identification in the concluding years of the last century, the mammalian transient receptor potential (canonical) (TRPC) channels have remained in the limelight as the primary candidates for the Ca(2+) entry pathway activated by the hormones, growth factors, and neurotransmitters that exert their effect through activation of PLC. Although TRPC channels have been shown clearly to mediate, at least in part, receptor-activated Ca(2+) entry in literally all cell types, several of their central characteristics, as recorded in expression systems using recombinant channels, differ from those of the native receptor-dependent Ca(2+) influx channels. The present review attempts to highlight the interaction of TRPC channels with other proteins, which may explain the variability of TRPC channel activation and regulatory mechanisms observed with the native and recombinant channels. These include the homologous and heterotopous interactions of TRPC channel isoforms, the interaction of TRPC channels with calmodulin, PLCgamma, IP(3) receptors, and with scaffolding proteins like InaD, EBP50/NEHRF, caveolin, Janctate and Homers.

Animals↗

PubMed1999

Leukotriene D4 (LTD4) activates charybdotoxin-sensitive and -insensitive K+ channels in ehrlich ascites tumor cells.

The putative role for ATP, UTP, bradykinin and leukotriene D4 (LTD4) in the activation of the charybdotoxin-insensitive, volume-activated K+ leak pathway has been assessed in Ehrlich cells. K+ channel activity is evaluated from bumetanide-insensitive 86Rb+ efflux using Rb+ as a tracer for K+. Addition of the Ca2+-mobilizing agonists bradykinin, ATP, UTP or LTD4 accelerates the regulatory volume decrease (RVD) response and activates a fast bumetanide-insensitive, charybdotoxin-sensitive efflux of K+. In addition LTD4 activates a charybdotoxin-insensitive K+ efflux, whereas bradykinin, ATP and UTP do not. The charybdotoxin-insensitive K+ efflux dominates after addition of LTD4 at concentrations too low to elicit an increase in [Ca2+]i but still high enough to be effective in accelerating the RVD response. The EC50 values for LTD4-induced K+ effluxes are estimated at 2 nM and 15 nM for the charybdotoxin-insensitive and charybdotoxin-sensitive components, respectively. The LTD4 (cysLT1) receptor antagonist L660,711(MK-571) blocks the activation of the charybdotoxin-sensitive but not the charybdotoxin-insensitive K+ efflux. Thus, LTD4 activates two different K+ leak pathways in Ehrlich cells, one pathway activated by an increase in [Ca2+]i and the other via an alternative signalling pathway. LTD4 is thus a potential candidate for an autocrine messenger activating the Ca2+-independent, charybdotoxin-insensitive K+ channel during the RVD response in Ehrlich cells.

Adenosine Triphosphate↗

PubMed2001

Zebrafish hybrids suggest genetic mechanisms for pigment pattern diversification in Danio.

Pigment patterns of Danio fishes are a tractable system for assessing the developmental genetic bases for the evolution of adult form in vertebrates. These pigment patterns include multiple horizontal melanophore stripes in the zebrafish D. rerio, a complete absence of stripes in D. albolineatus, a few broad stripes in D. kerri, and a combination of stripes and spots in D. nigrofasciatus. Here we assess the genetics of pigment pattern development and evolution using interspecific hybrids. We first reconstruct the phylogenetic relationships of these species by analyzing mitochondrial 12S and 16S rDNA sequences. We find a clade comprising several small species of danio, and within this clade a sister taxon relationship between D. rerio and D. nigrofasciatus. We also find that the large bodied D. dangila is more closely related to the clade of small danios than other large bodied species. As a first step in evaluating the genetics of pigment pattern diversification in the group, we then examine the phenotypes of interspecific hybrids. Adult pigment patterns of hybrids between D. rerio and other danios are in many respects more similar to D. rerio than the heterospecific danio, demonstrating that alleles of pigment pattern genes in other species typically are recessive to D. rerio alleles. Furthermore, hybrids between two additional striped species (D. kerri, D. nigrofasciatus) and D. albolineatus suggest that striped patterns are dominant or semi-dominant over an absence of stripes. Together, these analyses support a model in which pigment pattern differences between D. rerio and other species result from gain-of-function alleles in D. rerio, or loss-of-function alleles in other danios. Finally, because several D. rerio pigment pattern mutants resemble heterospecific danios, we use interspecific complementation tests to assess potential roles for these loci in pigment pattern diversification. Crosses between other danios and most D. rerio pigment pattern mutants develop stripes, similar to control hybrids with wild-type D. rerio. These complementation phenotypes allow us to exclude most of these loci as having major effect roles in generating pigment pattern differences between species. In contrast, hybrids between fms mutant D. rerio and D. albolineatus fail to develop stripes, similar to D. albolineatus. This non-complementation phenotype identifies changes in fms, or the pathway in which it acts, as candidates for contributing to the evolutionary loss of stripes in D. albolineatus.

Animals↗