title: Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye development.
abstract: Dicer, a ribonuclease essential for miRNA processing, is expressed abundantly in developing mouse cornea and lens. We studied the roles of Dicer and miRNAs in eye development by conditionally deleting the Dicer gene in the mouse lens and corneal epithelium. Adult Dicer conditional null (DicerCN) mice had severe microphthalmia with no discernible lens and a poorly stratified corneal epithelium. Targeted deletion of Dicer effectively inhibited miRNA processing in the developing lens at 12.5 day of embryogenesis (E12.5). Lens development initiated normally but underwent progressive dystrophy between E14.5 and E18.5. Microarray analysis revealed activation of P53 signaling in DicerCN lenses at E13.5, consistent with increased apoptosis and reduced cell proliferation between E12.5 and E14.5. Expression of Pax6 and other lens developmental transcription factors were not greatly affected between E12.5 and E14.5 but decreased as the lens degenerated. Our data indicated an indispensible role for Dicer and miRNAs in lens and corneal development.
authors.affiliation: Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. liyan2@mail.nih.gov
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Joram
authors.initials: J
authors.lastname: Piatigorsky
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000235:genetics / Q000502:physiology*; D019573:Epithelium, Corneal / Q000196:embryology / Q000378:metabolism*; D005123:Eye / Q000196:embryology / Q000378:metabolism*; D007150:Immunohistochemistry; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III
chemical_list: D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
references.citation: Circulation. 2008 Oct 7;118(15):1567-76
references.pmid: 18809798
references.citation: Int J Dev Biol. 2004;48(8-9):783-91
references.pmid: 15558471
references.citation: Nature. 2004 Sep 16;431(7006):364-70
references.pmid: 15372044
references.citation: Genes Cells. 1998 Dec;3(12):801-10
references.pmid: 10096021
references.citation: Nature. 2008 May 22;453(7194):539-43
references.pmid: 18404146
references.citation: Dev Biol. 2000 Apr 15;220(2):424-31
references.pmid: 10753528
references.citation: Semin Cell Dev Biol. 2006 Dec;17(6):726-40
references.pmid: 17116415
references.citation: Dev Biol. 2007 Nov 15;311(2):512-23
references.pmid: 17936264
references.citation: Nature. 2005 Feb 17;433(7027):769-73
references.pmid: 15685193
references.citation: Development. 2001 Nov;128(22):4425-38
references.pmid: 11714669
references.citation: Mol Vis. 2006 Oct 17;12:1175-84
references.pmid: 17102797
references.citation: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2006 Nov;150(2):205-15
references.pmid: 17426780
references.citation: Invest Ophthalmol. 1969 Feb;8(1):25-31
references.pmid: 5763845
references.citation: Mol Cell Biol. 2005 Feb;25(3):1191-9
references.pmid: 15657444
references.citation: Science. 2000 Jul 28;289(5479):631-3
references.pmid: 10915628
references.citation: Nature. 2005 Dec 1;438(7068):671-4
references.pmid: 16319892
references.citation: Cell. 2007 Apr 20;129(2):303-17
references.pmid: 17397913
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Int Rev Cytol. 1980;63:263-322
references.pmid: 395131
references.citation: Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3360-70
references.pmid: 18469187
references.citation: Nature. 1992 Sep 24;359(6393):295-300
references.pmid: 1406933
references.citation: Cell Cycle. 2006 Dec;5(23):2697-703
references.pmid: 17172853
references.citation: Nature. 1992 Sep 24;359(6393):288-94
references.pmid: 1406932
references.citation: Curr Biol. 2003 May 13;13(10):807-18
references.pmid: 12747828
references.citation: Mol Vis. 1998 Apr 30;4:8
references.pmid: 9565648
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16230-5
references.pmid: 18852463
references.citation: Trends Biochem Sci. 2007 Apr;32(4):189-97
references.pmid: 17350266
references.citation: Biosci Rep. 2001 Aug;21(4):537-63
references.pmid: 11900326
references.citation: BMC Dev Biol. 2006 Mar 15;6:14
references.pmid: 16539717
references.citation: Mol Vis. 2007 Dec 18;13:2289-300
references.pmid: 18199970
references.citation: Invest Ophthalmol Vis Sci. 2007 Feb;48(2):509-15
references.pmid: 17251443
references.citation: Dev Biol. 2009 Feb 15;326(2):403-17
references.pmid: 18996109
references.citation: Int J Dev Biol. 2004;48(8-9):857-65
references.pmid: 15558477
references.citation: Cell Stem Cell. 2008 Mar 6;2(3):219-29
references.pmid: 18371447
references.citation: J Med Genet. 2005 Sep;42(9):706-10
references.pmid: 16141006
references.citation: Nucleic Acids Res. 2005 Nov 27;33(20):e179
references.pmid: 16314309
references.citation: Bone. 2008 Jun;42(6):1025-31
references.pmid: 18396127
references.citation: Nature. 1992 Sep 24;359(6393):328-30
references.pmid: 1406937
references.citation: Cancer Res. 2006 Sep 1;66(17):8356-60
references.pmid: 16951143
references.citation: Cell. 2005 Nov 18;123(4):631-40
references.pmid: 16271387
references.citation: Nature. 2008 May 22;453(7194):534-8
references.pmid: 18404147
references.citation: Dev Biol. 2005 Apr 1;280(1):1-14
references.pmid: 15766743
references.citation: Int J Dev Biol. 2004;48(8-9):903-11
references.pmid: 15558481
references.citation: Jikken Dobutsu. 1988 Oct;37(4):455-62
references.pmid: 3149245
references.citation: Prog Retin Eye Res. 2007 Nov;26(6):555-97
references.pmid: 17905638
references.citation: EMBO J. 2004 Oct 13;23(20):4051-60
references.pmid: 15372072
references.citation: Prog Retin Eye Res. 1998 Apr;17(2):145-74
references.pmid: 9695791
references.citation: Science. 2000 Feb 11;287(5455):1040-6
references.pmid: 10669416
references.citation: Nat Genet. 1999 Sep;23(1):113-7
references.pmid: 10471511
references.citation: Cytokine Growth Factor Rev. 2002 Jun;13(3):199-207
references.pmid: 12486874
references.citation: Cell. 2005 Jan 14;120(1):15-20
references.pmid: 15652477
references.citation: Nature. 2002 Apr 25;416(6883):865-9
references.pmid: 11976687
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19300-5
references.pmid: 19033458
references.citation: Dev Biol. 2007 Nov 15;311(2):359-68
references.pmid: 17936265
references.citation: Dev Dyn. 2005 Jun;233(2):516-27
references.pmid: 15778993
references.citation: Mol Cell. 2001 Jul;8(1):85-94
references.pmid: 11511362
references.citation: Cell Cycle. 2008 Jun 1;7(11):1529-38
references.pmid: 18469525
references.citation: Dev Biol. 2000 Jun 1;222(1):110-23
references.pmid: 10885750
references.citation: Dev Dyn. 2008 Mar;237(3):602-17
references.pmid: 18224708
references.citation: Nature. 2007 Jun 28;447(7148):1130-4
references.pmid: 17554337
references.citation: Dev Biol. 2003 Mar 1;255(1):113-27
references.pmid: 12618137
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2111-6
references.pmid: 18256189
references.citation: Anat Embryol (Berl). 2001 Feb;203(2):77-87
references.pmid: 11218061
references.citation: Invest Ophthalmol Vis Sci. 1999 Dec;40(13):3075-8
references.pmid: 10586926
references.citation: Curr Biol. 2006 May 23;16(10):1041-9
references.pmid: 16682203
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18097-102
references.pmid: 17989215
references.citation: Cell. 2005 Aug 26;122(4):553-63
references.pmid: 16122423
references.citation: Circ Res. 2009 Apr 10;104(7):879-86
references.pmid: 19265035
references.citation: Genes Dev. 2000 Nov 1;14(21):2701-11
references.pmid: 11069887
references.citation: Development. 2002 Jun;129(12):2891-903
references.pmid: 12050137
references.citation: Dev Growth Differ. 2000 Oct;42(5):437-48
references.pmid: 11041485
references.citation: Science. 2005 Sep 2;309(5740):1573-6
references.pmid: 16081698
references.citation: Genes Dev. 2008 Oct 15;22(20):2773-85
references.pmid: 18923076
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12135-40
references.pmid: 16099834