RESUMO
Ryk is a member of the receptor tyrosine kinase (RTK) family of proteins that control and regulate cellular processes. It is distinguished by binding Wnt ligands and having no detectable intrinsic protein tyrosine kinase activity suggesting Ryk is a pseudokinase. Here, we show an essential role for Ryk in directing morphogenetic events required for normal cardiac development through the examination of Ryk-deficient mice. We employed vascular corrosion casting, vascular perfusion with contrast dye, and immunohistochemistry to characterize cardiovascular and pharyngeal defects in Ryk-/- embryos. Ryk-/- mice exhibit a variety of malformations of the heart and outflow tract that resemble human congenital heart defects. This included stenosis and interruption of the aortic arch, ventriculoarterial malalignment, ventricular septal defects and abnormal pharyngeal arch artery remodelling. This study therefore defines a key intersection between a subset of growth factor receptors involved in planar cell polarity signalling, the Wnt family and mammalian cardiovascular development.
Assuntos
Cardiopatias Congênitas/etiologia , Faringe/anormalidades , Receptores Proteína Tirosina Quinases/fisiologia , Proteínas Wnt/metabolismo , Animais , Aorta Torácica/anormalidades , Feminino , Camundongos , Morfogênese , GravidezRESUMO
Heterozygous germline mutations in the LKB1 (STK11) gene cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by hamartomatous polyposis of the gastrointestinal tract and an increased risk of colorectal, breast, and other cancers. To model the role of LKB1 mutation in mammary tumourigenesis, we have used a conditional gene targeting strategy to generate a mouse in which exons encoding the kinase domain of Lkb1 were deleted specifically in the mammary gland. Mammary gland tumours developed in these mice with a latency of 46-85 weeks and occurred in the thoracic or inguinal glands. These tumours were grade 2 invasive ductal carcinomas or solid papillary carcinomas with histological features similar to those described in breast cancers arising in patients with PJS. This mouse model of Lkb1 deficiency provides a potentially useful tool to investigate the role of Lkb1 in tumourigenesis and to guide the development of therapeutic approaches.
Assuntos
Deleção de Genes , Neoplasias Mamárias Experimentais/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Quinases Ativadas por AMP , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas de Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/deficiência , Receptores de Estrogênio/metabolismoRESUMO
The lymphatic network functions to return fluid, cells and macromolecules to the circulation. Recent characterization of growth factors that control the growth and development of the lymphatics, and markers which specify lymphatic endothelial cells have enhanced our understanding of this system. Members of the VEGF family of factors are key regulators of these vessels with VEGF-C/VEGF-D and VEGFR-3 being the best validated signalling pathways in lymphangiogenesis. The study of these molecules in various pathologies has shown that they are important in the processes of cancer metastasis and in the formation of lymphoedema. Knowledge of these molecular pathways allows for the generation of modulators of these pathways which could form the basis of novel therapeutic approaches.
Assuntos
Linfangiogênese/fisiologia , Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos , Linfangiogênese/genética , Transdução de Sinais/genéticaRESUMO
Deregulation of MYC expression occurs in many haematological malignancies. Previous studies modelling MYC-induced lymphomagenesis in the mouse used transgenic vectors that directed MYC overexpression in a lineage-specific manner. Here, we describe a transgenic mouse strain in which constitutive MYC expression is driven broadly in haemopoiesis by a vector containing regulatory elements of the Vav gene. Healthy young VavP-MYC17 mice had multiple haemopoietic abnormalities, most notably increased size and numbers of B-lymphoid cells, monocytes and megakaryocytes. The mice rapidly developed tumours and, surprisingly, these were exclusively T-cell lymphomas, mostly of mature CD4(+) CD8(-) T cells, a tumour type that is seldom seen in mouse models. To examine tumour development in the absence of the susceptible T cells, we bred VavP-MYC17 mice lacking the Rag1 recombinase. They survived longer and succumbed to tumours of several different haemopoietic cell types: pre-T cells, pro-B cells, macrophages and unusual progenitor cells. Thus, although T-lineage cells have the shortest latent period to transformation, the VavP-MYC17 transgene drives malignant transformation of multiple cell types and VavP-MYC17 mice provide a new model for tumours of multiple haemopoietic lineages.
Assuntos
Transformação Celular Neoplásica , Linfoma de Células T/patologia , Células Mieloides/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Linfócitos B/patologia , Linfócitos B/fisiologia , Western Blotting , Linhagem da Célula , Modelos Animais de Doenças , Citometria de Fluxo , Vetores Genéticos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Linfoma de Células T/genética , Megacariócitos/patologia , Megacariócitos/fisiologia , Camundongos , Camundongos Transgênicos , Monócitos/patologia , Monócitos/fisiologia , Células Mieloides/fisiologia , Proteínas Proto-Oncogênicas c-myc/genética , Vírus 40 dos Símios , TransgenesRESUMO
Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)-dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.