Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux
| Autor: | Carlton M. Bates, Sunder Sims-Lucas, Caitlin Schaefer, Whitney M. Sunseri, Feng Chen, Mark P. de Caestecker, Tatiana Novitskaya, Kenneth Walker, Valeria Di Giovanni |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Pathology
Anatomy and Physiology Mouse 030232 urology & nephrology lcsh:Medicine Fibroblast growth factor urologic and male genital diseases 0302 clinical medicine Molecular Cell Biology Morphogenesis lcsh:Science 0303 health sciences Multidisciplinary Cell Death Statistics Bladder and Ureteric Disorders Animal Models female genital diseases and pregnancy complications 3. Good health medicine.anatomical_structure Ureteric bud embryonic structures Medicine Immunohistochemical Analysis Research Article musculoskeletal diseases medicine.medical_specialty Histology Mesenchyme Urology Immunology Biology Biostatistics Vesicoureteral reflux Mesonephric duct 03 medical and health sciences Ureter Model Organisms Stroma medicine Genetics Birth Defects 030304 developmental biology Fibroblast growth factor receptor 2 lcsh:R Renal System medicine.disease stomatognathic diseases Genetics of Disease Immunologic Techniques lcsh:Q Gene Function Animal Genetics Mathematics Developmental Biology |
| Zdroj: | PLoS ONE, Vol 8, Iss 2, p e56062 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Purpose Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity. Methods We conditionally deleted Fgfr2 in ST (Fgfr2ST−/−) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects. Results We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2ST−/− mice at embryonic day (E) 10.5. E11.5 Fgfr2ST−/− mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2ST−/− mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2ST−/− mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes. Conclusion Mutations in FGFR2 could possibly cause VUR in humans. |
| Databáze: | OpenAIRE |
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