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XB-ART-48915
Proc Natl Acad Sci U S A. April 29, 2014; 111 (17): 6335-40.

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 .


Abstract
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: 5R21DK077763-02 NIDDK NIH HHS , R21 DK077763 NIDDK NIH HHS , 5R21DK077763-02 NIDDK NIH HHS

Genes referenced: actl6a akt1 atp1b1 dicer1 gnl3 igf1 igf1r igf2 igf3 ins insr insrr irs1 mtor mut pklr pten rps6 slc12a1 slc12a3 slc5a9 tsc1 tsc2

Antibodies referenced: Akt1 Ab7 Akt1 Ab8 Insr Ab1 Kidney Ab2 Mapk1 Ab16 Rps6 AB4 Rps6 Ab3 Somite Ab3 Tsc1 Ab
Morpholinos referenced: dicer1 MO5 igf2 MO1 ins MO1 pten MO1 tsc1 MO1

References:
Agrawal, 2009, Pubmed, Xenbase[+]


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