The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development
| Autor: | Wolfram Goessling, Rebecca A. Wingert, Ryan Thummel, Michael McKernan, Annemarie Fox, Gary F. Gerlach, Amanda N. Marra, Bridgette E. Drummond, Kristen K. McCampbell, Adriana Rodríguez-Marí, Paul T. Kroeger, Ignaty Leshchiner, Ruth Bremiller, John H. Postlethwait, Alan J. Davidson, Rachel Miceli |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Morpholino Organogenesis medicine.disease_cause Pronephros Article Morpholinos Podocyte Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Genetic model medicine Animals Cloning Molecular Molecular Biology Zebrafish In Situ Hybridization Fluorescence Cell Proliferation BRCA2 Protein Genetics Mutation Kidney biology Podocytes Gene Expression Regulation Developmental Cell Differentiation Cell Biology Zebrafish Proteins biology.organism_classification Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Interrenal Gland Developmental Biology |
| Zdroj: | Developmental Biology. 428:148-163 |
| ISSN: | 0012-1606 |
| DOI: | 10.1016/j.ydbio.2017.05.025 |
| Popis: | The zebrafish kidney is conserved with other vertebrates, making it an excellent genetic model to study renal development. The kidney collects metabolic waste using a blood filter with specialized epithelial cells known as podocytes. Podocyte formation is poorly understood but relevant to many kidney diseases, as podocyte injury leads to progressive scarring and organ failure. zeppelin (zep) was isolated in a forward screen for kidney mutants and identified as a homozygous recessive lethal allele that causes reduced podocyte numbers, deficient filtration, and fluid imbalance. Interestingly, zep mutants had a larger interrenal gland, the teleostean counterpart of the mammalian adrenal gland, which suggested a fate switch with the related podocyte lineage since cell proliferation and cell death were unchanged within the shared progenitor field from which these two identities arise. Cloning of zep by whole genome sequencing (WGS) identified a splicing mutation in breast cancer 2, early onset (brca2)/fancd1, which was confirmed by sequencing of individual fish. Several independent brca2 morpholinos (MOs) phenocopied zep, causing edema, reduced podocyte number, and increased interrenal cell number. Complementation analysis between zep and brca2ZM_00057434 -/- zebrafish, which have an insertional mutation, revealed that the interrenal lineage was expanded. Importantly, overexpression of brca2 rescued podocyte formation in zep mutants, providing critical evidence that the brca2 lesion encoded by zep specifically disrupts the balance of nephrogenesis. Taken together, these data suggest for the first time that brca2/fancd1 is essential for vertebrate kidney ontogeny. Thus, our findings impart novel insights into the genetic components that impact renal development, and because BRCA2/FANCD1 mutations in humans cause Fanconi anemia and several common cancers, this work has identified a new zebrafish model to further study brca2/fancd1 in disease. |
| Databáze: | OpenAIRE |
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