Betaglycan is required for the establishment of nephron endowment in the mouse

Kenneth Walker, Sunder Sims-Lucas, Georgina Caruana, Luise Cullen-McEwen, Jinhua Li, Mai Sarraj, John Bertram, Kaye Stenvers

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Abstract

Betaglycan is an accessory receptor for the transforming growth factor-beta (TGFbeta) superfamily, many members of which play key roles in kidney development. The purpose of this study was to define the role of this co-receptor on fetal murine kidney development. Stereological examination of embryonic and adult betaglycan heterozygous kidneys revealed augmented nephron number relative to littermate controls. Fetal heterozygous kidneys exhibited accelerated ureteric branching, which correlated with augmented nephron development at embryonic day (e) 15.5. In contrast, betaglycan null kidneys exhibited renal hypoplasia from e13.5 and reduced nephron number at e15.5. Quantitative real-time PCR analysis of e11.5-e14.5 kidneys demonstrated that heterozygous kidneys exhibited a transient decrease in Bmp4 expression at e11.5 and a subsequent cascade of changes in the gene regulatory network that governs metanephric development, including significant increases in Pax2, Eya1, Gdnf, Ret, Wnt4, and Wt1 expression. Conversely, gene expression in null kidneys was normal until e13.5, when significant reductions were detected in the expression of Bmp4 as well as other key metanephric regulatory genes. Tgfb1 and Tgfb2 mRNA expression was down-regulated in both nulls and heterozygotes at e13.5 and e14.5. The opposing morphological and molecular phenotypes in betaglycan heterozygote and null mutants demonstrate that the levels of betaglycan must be tightly regulated for optimal kidney development.
Original languageEnglish
Article numbere18723
Number of pages10
JournalPLoS ONE
Volume6
Issue number4
DOIs
Publication statusPublished - 2011

Cite this

Walker, K., Sims-Lucas, S., Caruana, G., Cullen-McEwen, L., Li, J., Sarraj, M., ... Stenvers, K. (2011). Betaglycan is required for the establishment of nephron endowment in the mouse. PLoS ONE, 6(4), [e18723]. https://doi.org/10.1371/journal.pone.0018723
Walker, Kenneth ; Sims-Lucas, Sunder ; Caruana, Georgina ; Cullen-McEwen, Luise ; Li, Jinhua ; Sarraj, Mai ; Bertram, John ; Stenvers, Kaye. / Betaglycan is required for the establishment of nephron endowment in the mouse. In: PLoS ONE. 2011 ; Vol. 6, No. 4.
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Betaglycan is required for the establishment of nephron endowment in the mouse. / Walker, Kenneth; Sims-Lucas, Sunder; Caruana, Georgina; Cullen-McEwen, Luise; Li, Jinhua; Sarraj, Mai; Bertram, John; Stenvers, Kaye.

In: PLoS ONE, Vol. 6, No. 4, e18723, 2011.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Walker, Kenneth

AU - Sims-Lucas, Sunder

AU - Caruana, Georgina

AU - Cullen-McEwen, Luise

AU - Li, Jinhua

AU - Sarraj, Mai

AU - Bertram, John

AU - Stenvers, Kaye

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AB - Betaglycan is an accessory receptor for the transforming growth factor-beta (TGFbeta) superfamily, many members of which play key roles in kidney development. The purpose of this study was to define the role of this co-receptor on fetal murine kidney development. Stereological examination of embryonic and adult betaglycan heterozygous kidneys revealed augmented nephron number relative to littermate controls. Fetal heterozygous kidneys exhibited accelerated ureteric branching, which correlated with augmented nephron development at embryonic day (e) 15.5. In contrast, betaglycan null kidneys exhibited renal hypoplasia from e13.5 and reduced nephron number at e15.5. Quantitative real-time PCR analysis of e11.5-e14.5 kidneys demonstrated that heterozygous kidneys exhibited a transient decrease in Bmp4 expression at e11.5 and a subsequent cascade of changes in the gene regulatory network that governs metanephric development, including significant increases in Pax2, Eya1, Gdnf, Ret, Wnt4, and Wt1 expression. Conversely, gene expression in null kidneys was normal until e13.5, when significant reductions were detected in the expression of Bmp4 as well as other key metanephric regulatory genes. Tgfb1 and Tgfb2 mRNA expression was down-regulated in both nulls and heterozygotes at e13.5 and e14.5. The opposing morphological and molecular phenotypes in betaglycan heterozygote and null mutants demonstrate that the levels of betaglycan must be tightly regulated for optimal kidney development.

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