Dominant effects of RET receptor misexpression and ligand-independent RET signaling on ureteric bud development
| Autor: | Vivette D. D'Agati, Chiann-mun Chen, Zaiqi Wu, Frank Costantini, Shankar Srinivas |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities endocrine system medicine.medical_specialty Glial Cell Line-Derived Neurotrophic Factor Receptors endocrine system diseases Transgene Mesenchyme Kidney development Mice Transgenic Nerve Tissue Proteins Kidney Ligands Mice Proto-Oncogene Proteins Internal medicine medicine Glial cell line-derived neurotrophic factor Animals Drosophila Proteins Glial Cell Line-Derived Neurotrophic Factor Nerve Growth Factors RNA Messenger Promoter Regions Genetic neoplasms Molecular Biology In Situ Hybridization Homeodomain Proteins Mice Knockout biology Histocytochemistry urogenital system Proto-Oncogene Proteins c-ret Gene Expression Regulation Developmental Receptor Protein-Tyrosine Kinases Cell biology Endocrinology medicine.anatomical_structure Ureteric bud morphogenesis Ureteric bud biology.protein Ureter Signal transduction Developmental Biology |
| Zdroj: | Scopus-Elsevier Europe PubMed Central |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.126.7.1375 |
| Popis: | During kidney development, factors from the metanephric mesenchyme induce the growth and repeated branching of the ureteric bud, which gives rise to the collecting duct system and also induces nephrogenesis. One signaling pathway known to be required for this process includes the receptor tyrosine kinase RET and co-receptor GFRα-1, which are expressed in the ureteric bud, and the secreted ligand GDNF produced in the mesenchyme. To examine the role of RET signaling in ureteric bud morphogenesis, we produced transgenic mice in which the pattern of RET expression was altered, or in which a ligand-independent form of RET kinase was expressed. The Hoxb7 promoter was used to express RET throughout the ureteric bud branches, in contrast to its normal expression only at the bud tips. This caused a variable inhibition of ureteric bud growth and branching reminiscent of, but less severe than, the RET knockout phenotype. Manipulation of the level of GDNF, in vitro or in vivo, suggested that this defect was due to insufficient rather than excessive RET signaling. We propose that RET receptors expressed ectopically on ureteric bud trunk cells sequester GDNF, reducing its availability to the normal target cells at the bud tips. When crossed to RET knockout mice, the Hoxb7/RET transgene, which encoded the RET9 isoform, supported normal kidney development in some RET−/− animals, indicating that the other major isoform, RET51, is not required in this organ. Expression of a Hoxb7/RET-PTC2 transgene, encoding a ligand-independent form of RET kinase, caused the development of abnormal nodules, outside the kidney or at its periphery, containing branched epithelial tubules apparently formed by deregulated growth of the ureteric bud. This suggests that RET signaling is not only necessary but is sufficient to induce ureteric bud growth, and that the orderly, centripetal growth of the bud tips is controlled by the spatially and temporally regulated expression of GDNF and RET. |
| Databáze: | OpenAIRE |
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