title: MicroRNAs are critical regulators of tuberous sclerosis complex and mTORC1 activity in the size control of the Xenopus kidney.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.
authors.forename: Daniel
authors.initials: D
authors.lastname: Romaker
authors.forename: Vikash
authors.initials: V
authors.lastname: Kumar
authors.forename: Débora M
authors.initials: DM
authors.lastname: Cerqueira
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Cox
authors.forename: Oliver
authors.initials: O
authors.lastname: Wessely
mesh_terms: D000818:Animals; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology* / Q000196:embryology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D018374:LLC-PK1 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000235:genetics*
chemical_list: D007328:Insulin; D035683:MicroRNAs; D046912:Multiprotein Complexes; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D007335:Insulin-Like Growth Factor II; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: amphibian; frog; organogenesis; pronephros
references.citation: Nat Rev Genet. 2012 Mar 13;13(4):271-82
references.pmid: 22411466
references.citation: Dev Dyn. 2011 Jun;240(6):1558-66
references.pmid: 21465621
references.citation: Curr Top Microbiol Immunol. 2010;347:263-78
references.pmid: 20473788
references.citation: Genes Dev. 2000 Nov 1;14(21):2689-94
references.pmid: 11069885
references.citation: Nat Cell Biol. 2012 Dec;14(12):1322-9
references.pmid: 23143395
references.citation: Cell. 2011 Sep 30;147(1):81-94
references.pmid: 21962509
references.citation: Curr Biol. 2012 May 8;22(9):R368-79
references.pmid: 22575479
references.citation: Nat Rev Drug Discov. 2006 Aug;5(8):671-88
references.pmid: 16883305
references.citation: Pediatr Nephrol. 2014 Apr;29(4):575-80
references.pmid: 24022365
references.citation: Dev Biol. 2004 Jul 15;271(2):322-38
references.pmid: 15223337
references.citation: Dev Cell. 2001 Nov;1(5):655-65
references.pmid: 11709186
references.citation: Trends Cell Biol. 2003 Feb;13(2):79-85
references.pmid: 12559758
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Development. 2010 Jun;137(11):1863-73
references.pmid: 20431116
references.citation: Nature. 2010 Jun 24;465(7301):1033-8
references.pmid: 20577206
references.citation: Oncogene. 2005 Nov 14;24(50):7475-81
references.pmid: 16288294
references.citation: In Vitro. 1976 Oct;12(10):670-7
references.pmid: 828141
references.citation: Nat Cell Biol. 2002 Sep;4(9):658-65
references.pmid: 12172554
references.citation: Neuron. 2010 Feb 11;65(3):341-57
references.pmid: 20159448
references.citation: J Clin Invest. 2001 Nov;108(9):1359-67
references.pmid: 11696581
references.citation: Cell. 2012 Mar 16;148(6):1172-87
references.pmid: 22424228
references.citation: Dev Biol. 1995 Oct;171(2):531-40
references.pmid: 7556934
references.citation: Lancet. 1999 May 22;353(9166):1789-92
references.pmid: 10348008
references.citation: Mech Dev. 1997 Nov;68(1-2):45-57
references.pmid: 9431803
references.citation: Endocrinology. 2013 Apr;154(4):1434-43
references.pmid: 23456362
references.citation: Dev Biol. 2007 Jul 1;307(1):152-64
references.pmid: 17521625
references.citation: Dev Biol. 2006 Sep 1;297(1):103-17
references.pmid: 16872594
references.citation: Nat Cell Biol. 2002 Sep;4(9):648-57
references.pmid: 12172553
references.citation: Nat Rev Mol Cell Biol. 2010 Apr;11(4):252-63
references.pmid: 20216554
references.citation: Dev Biol. 2013 Apr 1;376(1):31-42
references.pmid: 23352791
references.citation: J Embryol Exp Morphol. 1962 Mar;10:103-14
references.pmid: 13894369
references.citation: Sci Transl Med. 2011 Feb 16;3(70):70ra13
references.pmid: 21325617
references.citation: Curr Opin Cell Biol. 2012 Apr;24(2):194-201
references.pmid: 22196932
references.citation: J Med Chem. 2011 Mar 10;54(5):1473-80
references.pmid: 21322566
references.citation: Kidney Int. 2008 May;73(10):1120-7
references.pmid: 18322540
references.citation: Methods Mol Biol. 2012;886:121-32
references.pmid: 22639256
references.citation: N Engl J Med. 2003 Jan 9;348(2):101-8
references.pmid: 12519920
references.citation: Mol Cell. 2002 Jul;10(1):151-62
references.pmid: 12150915
references.citation: Biochim Biophys Acta. 2010 Apr;1802(4):396-405
references.pmid: 20079433
references.citation: Cell Cycle. 2009 Aug 15;8(16):2502-8
references.pmid: 19597332
references.citation: Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
references.pmid: 19339977
references.citation: Genes Dev. 2002 Nov 15;16(22):2958-70
references.pmid: 12435636
references.citation: Mech Dev. 2003 Nov;120(11):1283-96
references.pmid: 14623438
references.citation: Development. 2009 Dec;136(23):3927-36
references.pmid: 19906860
references.citation: Pediatr Nephrol. 2011 Sep;26(9):1545-51
references.pmid: 21499947