Sonic Hedgehog Protein Regulates Fibroblast Growth Factor 8 Expression in Metanephric Explant Culture from BALB/c Mice: Possible Mechanisms Associated with Renal Morphogenesis

Overview

Journal Mol Med Rep

Specialty Molecular Biology

Date 2016 Aug 12

PMID 27510750

Citations 1

Authors

Xing Chen

Xiao-Ming Hou

You-Fei Fan

Yu-Ting Jin

Yu-Lin Wang

Affiliations

Soon will be listed here.

Abstract

The sonic hedgehog (SHH) morphogen regulates cell differentiation and controls a number of genes during renal morphogenesis. To date, the effects of SHH on fibroblast growth factors (Fgfs) in embryonic kidney development remain unclear. In the present study, explants of BALB/c mouse embryonic kidney tissues were used to investigate the role of exogenous SHH on Fgf8 and Fgf10 expression levels ex vivo. Ureteric bud branches and epithelial metanephric derivatives were used to determine the renal morphogenesis with Dolichos biflorus agglutinin or hematoxylin‑eosin staining. mRNA expression levels were determined using reverse transcription‑quantitative polymerase chain reaction, while the protein expression levels were examined using immunohistochemistry and western blot analysis. During the initial stages of metanephric development, low levels of SHH, Fgf8, and Fgf10 expression were observed, which were found to increase significantly during more advanced stages of metanephric development. In addition, exogenous SHH protein treatment increased the number of ureteric bud branches and enhanced the formation of nephrons. Exogenous SHH reduced the Fgf8 mRNA and protein expression levels, whereas cyclopamine (an SHH‑smoothened receptor inhibitor) interfered with SHH‑mediated downregulation of Fgf8 expression. By contrast, exogenous SHH protein was not found to modulate Fgf10 mRNA and protein expression levels. In conclusion, these results indicate that the modulatory effects of SHH on BALB/c mouse metanephric explant cultures may involve the regulation of Fgf8 expression but not Fgf10 expression, which provides evidence for the functional role of Fgf proteins in renal morphogenesis.

Citing Articles

Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone.

Minuth W Mol Cell Pediatr. 2017; 4(1):12.

PMID: 29218481 PMC: 5721096. DOI: 10.1186/s40348-017-0078-6.

References

Shah M, Sampogna R, Sakurai H, Bush K, Nigam S . Branching morphogenesis and kidney disease. Development. 2004; 131(7):1449-62. DOI: 10.1242/dev.01089. View

Chai L, Yang J, Di C, Cui W, Kawakami K, Lai R . Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development. J Biol Chem. 2006; 281(28):18918-26. DOI: 10.1074/jbc.M600180200. View

Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T . Fgf10 is essential for limb and lung formation. Nat Genet. 1999; 21(1):138-41. DOI: 10.1038/5096. View

Grieshammer U, Cebrian C, Ilagan R, Meyers E, Herzlinger D, Martin G . FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons. Development. 2005; 132(17):3847-57. DOI: 10.1242/dev.01944. View

Guo W, Yi X, Ren F, Liu L, Wu S, Yang J . Activation of SHH signaling pathway promotes vasculogenesis in post-myocardial ischemic-reperfusion injury. Int J Clin Exp Pathol. 2016; 8(10):12464-72. PMC: 4680378. View

Barasch J, Qiao J, McWilliams G, Chen D, Oliver J, Herzlinger D . Ureteric bud cells secrete multiple factors, including bFGF, which rescue renal progenitors from apoptosis. Am J Physiol. 1997; 273(5):F757-67. DOI: 10.1152/ajprenal.1997.273.5.F757. View

Poladia D, Kish K, Kutay B, Hains D, Kegg H, Zhao H . Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol. 2006; 291(2):325-39. DOI: 10.1016/j.ydbio.2005.12.034. View

Park H, Bai C, Platt K, Matise M, Beeghly A, Hui C . Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development. 2000; 127(8):1593-605. DOI: 10.1242/dev.127.8.1593. View

Reidy K, Rosenblum N . Cell and molecular biology of kidney development. Semin Nephrol. 2009; 29(4):321-37. PMC: 2789488. DOI: 10.1016/j.semnephrol.2009.03.009. View

10.

Bai C, Auerbach W, Lee J, Stephen D, Joyner A . Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development. 2002; 129(20):4753-61. DOI: 10.1242/dev.129.20.4753. View

11.

Xu X, Weinstein M, Li C, Naski M, Cohen R, Ornitz D . Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development. 1998; 125(4):753-65. DOI: 10.1242/dev.125.4.753. View

12.

Urban A, Zhou X, Ungos J, Raible D, Altmann C, Vize P . FGF is essential for both condensation and mesenchymal-epithelial transition stages of pronephric kidney tubule development. Dev Biol. 2006; 297(1):103-17. DOI: 10.1016/j.ydbio.2006.04.469. View

13.

Watanabe Y, Miyagawa-Tomita S, Vincent S, Kelly R, Moon A, Buckingham M . Role of mesodermal FGF8 and FGF10 overlaps in the development of the arterial pole of the heart and pharyngeal arch arteries. Circ Res. 2009; 106(3):495-503. PMC: 2843098. DOI: 10.1161/CIRCRESAHA.109.201665. View

14.

Zhang Z, Verheyden J, Hassell J, Sun X . FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds. Dev Cell. 2009; 16(4):607-13. PMC: 3541528. DOI: 10.1016/j.devcel.2009.02.008. View

15.

Murashima A, Akita H, Okazawa M, Kishigami S, Nakagata N, Nishinakamura R . Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm. Dev Biol. 2013; 386(1):216-26. PMC: 3985168. DOI: 10.1016/j.ydbio.2013.12.026. View

16.

Kim P, Mo R, Hui Cc C . Murine models of VACTERL syndrome: Role of sonic hedgehog signaling pathway. J Pediatr Surg. 2001; 36(2):381-4. DOI: 10.1053/jpsu.2001.20722. View

17.

White A, Xu J, Yin Y, Smith C, Schmid G, Ornitz D . FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development. 2006; 133(8):1507-17. DOI: 10.1242/dev.02313. View

18.

Michos O, Cebrian C, Hyink D, Grieshammer U, Williams L, DAgati V . Kidney development in the absence of Gdnf and Spry1 requires Fgf10. PLoS Genet. 2010; 6(1):e1000809. PMC: 2797609. DOI: 10.1371/journal.pgen.1000809. View

19.

Yu J, Carroll T, McMahon A . Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development. 2002; 129(22):5301-12. DOI: 10.1242/dev.129.22.5301. View

20.

Igarashi M, Finch P, Aaronson S . Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7). J Biol Chem. 1998; 273(21):13230-5. DOI: 10.1074/jbc.273.21.13230. View