Characterizing a rat Brca2 knockout model

Cotroneo, Michelle S.; Haag, Jill D.; Zan, Yunhong; Lopez, Christian; Thuwajit, Peti; Petukhova, Galina V.; Camerini‐Otero, R. Daniel; Gendron‐Fitzpatrick, Annette; Griep, Anne E.; Murphy, Christopher J.; Dubielzig, Richard R.; Gould, Michael N.

doi:10.1038/sj.onc.1209960

Cited by 30 publications

(23 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is intriguing that zep display renal failure and is embryonic lethal, features that are distinct from brca2 Q658X and brca2 ZM_00057434 . Across vertebrate models to date, BRCA2 null alleles are embryonic lethal in mouse and humans while viable in rats (Moynahan, 2002; Cotroneo, et al, 2007). Identification of whether zep represents a genetic null, hypomorphic, or hypermorphic allele will require many additional studies, and these will be necessary to further elucidate the molecular consequences that lead to the zep phenotype.…”

Section: Discussionmentioning

confidence: 99%

The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development

Kroeger

Drummond

Miceli

et al. 2017

Developmental Biology

View full text Add to dashboard Cite

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 telostean 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 model to further study brca2/fancd1 in disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development

Kroeger

Drummond

Miceli

et al. 2017

Developmental Biology

View full text Add to dashboard Cite

show abstract

“…Full length Brca2 protein was identified from testicular extracts from Brca2 +/+ and Brca2 +/-rats, and was absent in Brca2 -/-testes, providing validation of this model and a unique opportunity to assess Brca2-associated breast cancer susceptibility [52].…”

Section: Phenotype Of Brca1 and Brca2 Mutant Ratsmentioning

confidence: 99%

“…Phenotypic evaluation of Brca2 -/-rats having the SD genetic background revealed several abnormalities [52]. Compared with Brca2 +/+ and Brca2 +/-littermates, Brca2 -/-rats were significantly smaller and were infertile, as a consequence of impaired gonad Gould, Michael N. W81XWH-04-1-0436 development.…”

Section: Phenotype Of Brca1 and Brca2 Mutant Ratsmentioning

confidence: 99%

“…The underdeveloped mammary glands of Brca2 -/-female rats are estrogen responsive, as short-term estrogen replacement using implants following ovariectomy induced ductal elongation and branching morphogenesis [52]. Since it is difficult to mimic normal ovarian hormone secretion in a long-term fashion to allow for mammary carcinoma development, other methods were needed to correct the ovarian defect in Brca2 -/-rats.…”

Section: Strategies For Mammary Carcinoma Induction In Brca2 -/-Ratsmentioning

confidence: 99%

See 1 more Smart Citation

Characterizing a Rat Brca2 Knockout Model

Gould¹

2007

View full text Add to dashboard Cite

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 01-05-20072. REPORT TYPE (From -To) Final DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER University of WisconsinMadison, Wisconsin 53706-1490 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTBrca2 mutation carriers, while rare in the population, have a high probability to develop breast cancer. In order to better understand the etiology of this disease, as well as to develop pre-vention and treatment strategies for it, we require good animal models. In this project we character-ized the first rat knockout produced, which was that of the Brca2 locus. We showed that Brca2-/-rats survive and develop multiple cancers, but not breast cancer. The lack of breast cancer was likely due to a Brca2-/-associated lack of ovarian follicular development. We developed two approaches to address this problem using inbred WF rats on which this knockout allele was placed. The first involved trans-planting wild-type ovaries to knockout rats. Brca2-/-rats having wild type ovaries did not develop mammary carcinomas, due to regression of the transplanted tissue over time. The alternative strategy was to transplant mammary glands from Brca2-/-rats into wild type rats. Brca2-/-mammary glands did not develop carcinomas when transplanted into wild type recipients. However their morphologic characteris-tics differed from wild type transplants, showing a higher degree of branching and lobularity. As an alternative to these transplant models, we induced mammary carcinomas in Brca2+/-and Brca2+/+ controls with 7,12,dimethylbenz(a)anthracene (DMBA) and nitrosomethylurea (NMU), but found no differences in tumor multiplicity between the two genotypes. Although we were unable to produce a mammary tumor model, the Brca2-/-knockout rat provides a valuable complement to existing mouse models to st...

show abstract

“…Animals have a substantial reduction in lifespan that could be due, at least in part, to an increase in cancer development in multiple organs (stomach, bone, ovary, etc.). Tumors arising most frequently were osteosarcomas and ovarian tumors [10]. The exhaustive genetic analysis of breast cancer patients, which allow us to identify novel mutations, together with the use of animal models is a two-way road.…”

mentioning

confidence: 99%