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miRNA‐Mediated Regulation of mTORC1 is Important for the Growth of Proximal Tubules in the Mouse Metanephric Kidney
Author(s) -
Kumar Vikash,
Hassey Jessie,
Romaker Daniel,
Wessley Oliver
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.814.8
Subject(s) - mtorc1 , microbiology and biotechnology , biology , microrna , cell growth , nephron , xenopus , signal transduction , kidney development , pi3k/akt/mtor pathway , kidney , endocrinology , genetics , gene , embryonic stem cell
We recently demonstrated that the interplay between miRNAs and mTORC1 signaling is critical for organ size control in the Xenopus kidney. However, the mechanisms and signaling pathways determining the size of nephrons in metanephric kidney are poorly understood. Here we report that the growth of the proximal tubules is regulated by cell proliferation and hypertrophy. Like in Xenopus , mTORC1 signaling is a key pathway regulating hyperplasia and hypertrophy. Knockdown of Raptor, a key mTORC1 component, in early nephron precursors greatly reduced cell proliferation in the proximal tubules. To investigate a contribution of miRNAs, we focused on Tsc1, a well‐established key negative regulator of mTORC1 pathway. In silico analysis identified many miRNAs binding site on mouse Tsc1 3'‐UTR, some of which were functionally validated by dual luciferase assay. Genetic studies using Ago2 mutant mice, a key protein in miRNA activity, demonstrate that miRNAs control nephron size by increasing the cell cycle length. Together these results suggest that mTORC1 plays an important role in regulating cell proliferation and hypertrophy in the growth of metanephric proximal tubules and miRNAs are instrumental in fine tuning of this process.