In cattle, base color is attributed to activity at the melanocortin-1 receptor (MC1R), historically termed the extension locus, with alleles coding for black (ED), red (e), and wild-type (E+). These alleles, in most mammals, are presumed to follow the dominance model ED > E+ > e, although exceptions are often seen. In Bos indicus x Bos taurus F2 cattle, EDE+ heterozygotes observed were discordant with the dominance series for the MC1R alleles and displayed various degrees of reddening on an otherwise predicted black background. The objective of this study was to identify loci modifying black coat color in these individuals. The hypothesis was that degree of reddening was a quantitative trait controlled by multiple genes of small effect. Reddening was classified utilizing photographs for 5 subjective scoring systems and analyzed by general linear model procedures of SAS with fixed effects of sex, sire, family nested within sire, season of photo, and spotted status. Residuals from these models were utilized for interval analyses to identify quantitative trait loci (QTL). Analyses of 19 bovine autosomal chromosomes, identified chromosome-wise suggestive (P < 0.05) and significant (P < 0.01) QTL on bovine chromosomes (BTA) 4, 5, 15, 18, 21, 27, and 29. Unexpectedly, there was evidence of a major gene (F = 67.88) affecting reddening at 71 Mb of BTA 6 (based on build Btau4.0 of the bovine genome sequence) that accounted for 61.1% of the variation in reddening. This QTL coincided closely with a cluster of tyrosine kinase receptor genes (PDGFRA, KIT and KDR). Fitting SNP haplotypes for a 1 Mb region containing all 3 genes and centered on KIT accounted for all the variation attributed to this QTL. These data suggested that one of these 3 genes, or a gene in high linkage disequilibrium with them, was responsible for the majority of variation in degree of reddening. Two recombinants within this region identified PDGFRA as the strongest candidate gene. Functional analyses will be required to verify the role of PDGFRA and its interaction with MC1R to modify black coat color of Bos indicus influenced cattle.

Le réarrangement FIP1L1-PDGFRA (F/P), identifié de manière récurrente dans les leucémies chroniques à éosinophiles, est à l’origine d’une activation constitutive de l’activité tyrosine kinase de la chaîne &#945; du récepteur au PDGFR. Les mécanismes concourant à la prolifération éosinophile exclusive et au profil de cytotoxicité spécifique à cette leucémie sont encore mal élucidés. Ce récepteur PDGFRα;, principalement exprimé dans les cellules mésenchymateuses, y exerce des effets prolifératifs et chimiotactiques, en partie induits par la production intracellulaire de dérivés réactifs de l’oxygène (ROS). Ces constatations nous ont amené à étudier les perturbations du métabolisme oxydatif dans la leucémie F/P+, en utilisant une approche d’étude globale du protéome d’éosinophiles de sujets F/P+, comparé à des éosinophiles de sujets contrôles. Dans ce travail, nous avons démontré qu’il existe, dans les éosinophiles F/P+, une dérégulation de nombreuses protéines impliquées dans la signalisation redox intracellulaire. De plus, les modifications d’expression de certaines d’entre elles (peroxiredoxine-2, src-homology-2 domain containing tyrosine phosphatase-1 ou SHP-1), non retrouvées dans les éosinophiles de patients ayant un syndrome hyperéosinophilique idiopathique, et identifiées dans une lignée cellulaire exprimant F/P, semblent spécifiquement induites par F/P. L’activation du PDGFRα; dans les éosinophiles F/P+ est donc à l’origine d’un déséquilibre du métabolisme oxydatif dont les conséquences sur la différenciation vers le lignage éosinophile ou sur la cytotoxicité seront discutées. / The FIP1L1-PDGFRA (F/P) fusion gene, identified as a recurrent molecular finding in chronic eosinophilic leukemia, induces a constitutive activation of the kinase domain of PDGFR&#945;. However, the molecular events contributing to the predominant eosinophil lineage expansion and to the singular cytotoxicity profile of eosinophils in this leukemia remain unclear. PDGFRα;, mainly expressed in mesenchymal cells, possesses proliferative and chemotactic properties, which are, in part, mediated by the intracellular production of reactive oxygen species (ROS). These observations prompted us to investigate the disturbances of the redox signaling in the F/P-associated leukemia, using a comparative study of the proteome of F/P+-eosinophils and eosinophils of healthy controls. Here, we report, in F/P+-eosinophils, the abnormal expression of numerous proteins implicated in oxidative metabolism. Furthermore, changes in expression of particular proteins (peroxiredoxine-2 and src-homology-2 domain containing tyrosine phosphatase-1) appears specific to F/P-Eos compared to patients with idiopathic hypereosinophilic syndrome, and could be demonstrated in F/P-expressing cell line EOL-1. Thus, the activation of PDGFRα; in F/P+-eosinophils leads to a global disturbance of the redox signaling, whose consequences on the differentiation toward eosinophil lineage and cytotoxicity will be discussed.

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<p>Platelet-derived growth factor receptor α (PDGFRα) plays an important role during embryogenesis. After implantation, the patterns of expression of Pdgfrα and its ligand Pdgf-A undergo an "autocrine-paracrine transition", in that Pdgf-A becomes expressed in the ectoderm and epithelia, while Pdgfrα is expressed in the adjacent mesenchymal tissue. In human tumors, such as malignant glioma, both PDGF and PDGFRα are overexpressed within the same tissue, indicating that an autocrine PDGF loop is generated in the tumors. This thesis is focused on the <i>in vivo</i> functionality of the <i>PDGFR</i>α gene (<i>PDGFRA</i>) promoter, arid on the effect of autocrine PDGF-A stimulation in transgenic n-iice during embryogenesis. </p><p>To test the <i>in vivo</i> promoter function of a human PDGFRA 2.2 kb 5' flanking fragment, we generated transgenic mouse lines and found that the 2.2 kb fragment was able to promote lacZ reporter gene expression in most of the endogenous Pdgfra expressing tissues. Absence of expression and "ectopic" expression of the transgenic lacZ were also observed. To investigate the autocrine PDGF effect, we produced autocrine PDGF-As (A short-chain) transient transgenic embryos. These transgenic embryos carried a 6 kb mouse <i>Pdgfra</i> 5' flanking sequence linked to a human PDGF-As cDNA. The pattern of expression of the PDGF-As transgene mRNA was similar to that of lacZ. Some of the transgenic embryos exhibited severe abnormal phenotypes, such as midline fusion defects in the cephalic and craniofacial region and small body size, and these embryos die at mid-gestation stage. These findings indicate that a paracrine pattern of expression and the dosage of PDGF are important for sustaining normal embryo development, especially with regard to the middline fusion in craniofacial regions. </p><p>The possible signaling pathways that may be involved in regulating <i>Pdgfra</i> activity were also studied by comparison of patterns of mRNA expression of Gli, Ptc, and Paxl with that of Pdgfra. The results pointed to the possibility that the Shh signaling pathway may be involved in the regulation of <i>Pdgfra</i> expression for example during early bone and foregut development. The specific regulatory mechanisms may vary for different tissues.</p>

Platelet-derived growth factor receptor α (PDGFRα) plays an important role during embryogenesis. After implantation, the patterns of expression of Pdgfrα and its ligand Pdgf-A undergo an "autocrine-paracrine transition", in that Pdgf-A becomes expressed in the ectoderm and epithelia, while Pdgfrα is expressed in the adjacent mesenchymal tissue. In human tumors, such as malignant glioma, both PDGF and PDGFRα are overexpressed within the same tissue, indicating that an autocrine PDGF loop is generated in the tumors. This thesis is focused on the in vivo functionality of the PDGFRα gene (PDGFRA) promoter, arid on the effect of autocrine PDGF-A stimulation in transgenic n-iice during embryogenesis. To test the in vivo promoter function of a human PDGFRA 2.2 kb 5' flanking fragment, we generated transgenic mouse lines and found that the 2.2 kb fragment was able to promote lacZ reporter gene expression in most of the endogenous Pdgfra expressing tissues. Absence of expression and "ectopic" expression of the transgenic lacZ were also observed. To investigate the autocrine PDGF effect, we produced autocrine PDGF-As (A short-chain) transient transgenic embryos. These transgenic embryos carried a 6 kb mouse Pdgfra 5' flanking sequence linked to a human PDGF-As cDNA. The pattern of expression of the PDGF-As transgene mRNA was similar to that of lacZ. Some of the transgenic embryos exhibited severe abnormal phenotypes, such as midline fusion defects in the cephalic and craniofacial region and small body size, and these embryos die at mid-gestation stage. These findings indicate that a paracrine pattern of expression and the dosage of PDGF are important for sustaining normal embryo development, especially with regard to the middline fusion in craniofacial regions. The possible signaling pathways that may be involved in regulating Pdgfra activity were also studied by comparison of patterns of mRNA expression of Gli, Ptc, and Paxl with that of Pdgfra. The results pointed to the possibility that the Shh signaling pathway may be involved in the regulation of Pdgfra expression for example during early bone and foregut development. The specific regulatory mechanisms may vary for different tissues.

Background: GISTs are gastrointestinal mesenchymal tumours that express the type III receptor tyrosine kinase KIT. The KIT proto-oncogene encodes the receptor KIT. Most GISTs have gain-of-function mutations in the KIT or PDGFRA gene. The tyrosine kinase is therefore continuously activated leading to ligand-independent dimerization. Imatinib mesylate (Glivec®) is considered to be the first-line palliative treatment. The activated form of the KIT receptor tyrosine kinase is inhibited by imatinib. The aim of the study was to compare the survival of patients treated with either adjuvant or down-staging imatinib with historic controls treated with radical surgery (R0) only. Methods: A historic control group was chosen from a population-based series from western Sweden (population 1.6 million) that matched the adjuvant (n=23) and down-staging (n=7) groups respectively. Mutation analysis was performed in all cases with bidirectional direct sequencing. The recurrence-free survival was calculated. Results: There was only one recurrence (4 %) in the adjuvant group, and no recurrences in the down-staging study group, compared to 32/48 patients (67 %) in the control group. Tumour size decreased in diameter from 20 cm to 11 cm with down-staging treatment. Conclusion: Adjuvant imatinib improves recurrence-free survival in R0 resected patients. Down-staging treatment with imatinib is recommended for patients with large tumours or metastases. The importance of mutation analysis was established.

<p>Background: GISTs are gastrointestinal mesenchymal tumours that express the type III receptor tyrosine kinase KIT. The KIT proto-oncogene encodes the receptor KIT. Most GISTs have gain-of-function mutations in the KIT or PDGFRA gene. The tyrosine kinase is therefore continuously activated leading to ligand-independent dimerization. Imatinib mesylate (Glivec®) is considered to be the first-line palliative treatment. The activated form of the KIT receptor tyrosine kinase is inhibited by imatinib. The aim of the study was to compare the survival of patients treated with either adjuvant or down-staging imatinib with historic controls treated with radical surgery (R0) only.</p><p>Methods: A historic control group was chosen from a population-based series from western Sweden (population 1.6 million) that matched the adjuvant (n=23) and down-staging (n=7) groups respectively. Mutation analysis was performed in all cases with bidirectional direct sequencing. The recurrence-free survival was calculated.</p><p>Results: There was only one recurrence (4 %) in the adjuvant group, and no recurrences in the down-staging study group, compared to 32/48 patients (67 %) in the control group. Tumour size decreased in diameter from 20 cm to 11 cm with down-staging treatment.</p><p>Conclusion: Adjuvant imatinib improves recurrence-free survival in R0 resected patients. Down-staging treatment with imatinib is recommended for patients with large tumours or metastases. The importance of mutation analysis was established.</p>

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