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Proc Natl Acad Sci U S A 2014 Apr 29;11117:6335-40. doi: 10.1073/pnas.1320577111.
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MicroRNAs are critical regulators of tuberous sclerosis complex and mTORC1 activity in the size control of the Xenopus kidney.

Romaker D , Kumar V , Cerqueira DM , Cox RM , Wessely O .

MicroRNAs (miRNAs) are major posttranscriptional regulators of a wide variety of biological processes. However, redundancy among most miRNAs has made it difficult to identify their in vivo functions. We previously demonstrated that global inhibition of miRNA biogenesis in Xenopus resulted in a dramatically smaller pronephric kidney. This suggested that microRNAs play a pivotal role in organ size control. Here we now provide a detailed mechanistic explanation for this phenotype. We identified that the activation of the mechanistic target of rapamycin complex 1 (mTORC1) by Insulin and insulin-like growth factor (Igf) 2 is an important regulator in kidney growth, which in turn is modulated by microRNAs. Molecular analyses demonstrate that microRNAs set a threshold for mTORC1 signaling by down-regulating one of its core negative regulators, tuberous sclerosis 1 (Tsc1). Most importantly, this rheostat can be reprogrammed experimentally. Whereas knockdown of miRNAs causes growth arrest, concomitant knockdown of Tsc1 restores mTORC1 activity and proximal tubular size. Together, these data establish a previously unidentified in vivo paradigm for the importance of posttranscriptional regulation in organ size control.

PubMed ID: 24733901
PMC ID: PMC4036005
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus
Genes referenced: actl6a atp1b1 dicer1 hk2 hook2 igf1 igf1r igf2 igf3 ins insr insrr irs1 mmut mtor pklr pten rps6 slc12a1 slc12a3 slc5a9 smo tsc1 tsc2
Antibodies: Akt1 Ab7 Akt1 Ab8 Insr Ab1 Kidney Ab2 Mapk1 Ab16 Rps6 AB4 Rps6 Ab3 Somite Ab3 Tsc1 Ab
Morpholinos: dicer1 MO5 igf2 MO1 ins MO1 pten MO1 tsc1 MO1

Phenotypes: Xla Wt + LY294002 (fig.2.f) [+]

Article Images: [+] show captions
References [+] :
Agrawal, The miR-30 miRNA family regulates Xenopus pronephros development and targets the transcription factor Xlim1/Lhx1. 2009, Pubmed, Xenbase