title: Increased corneal epithelial turnover contributes to abnormal homeostasis in the Pax6(+/-) mouse model of aniridia.
abstract: We aimed to test previous predictions that limbal epithelial stem cells (LESCs) are quantitatively deficient or qualitatively defective in Pax6(+/-) mice and decline with age in wild-type (WT) mice. Consistent with previous studies, corneal epithelial stripe patterns coarsened with age in WT mosaics. Mosaic patterns were also coarser in Pax6(+/-) mosaics than WT at 15 weeks but not at 3 weeks, which excludes a developmental explanation and strengthens the prediction that Pax6(+/-) mice have a LESC-deficiency. To investigate how Pax6 genotype and age affected corneal homeostasis, we compared corneal epithelial cell turnover and label-retaining cells (LRCs; putative LESCs) in Pax6(+/-) and WT mice at 15 and 30 weeks. Limbal BrdU-LRC numbers were not reduced in the older WT mice, so this analysis failed to support the predicted age-related decline in slow-cycling LESC numbers in WT corneas. Similarly, limbal BrdU-LRC numbers were not reduced in Pax6(+/-) heterozygotes but BrdU-LRCs were also present in Pax6(+/-) corneas. It seems likely that Pax6(+/-) LRCs are not exclusively stem cells and some may be terminally differentiated CD31-positive blood vessel cells, which invade the Pax6(+/-) cornea. It was not, therefore, possible to use this approach to test the prediction that Pax6(+/-) corneas had fewer LESCs than WT. However, short-term BrdU labelling showed that basal to suprabasal movement (leading to cell loss) occurred more rapidly in Pax6(+/-) than WT mice. This implies that epithelial cell loss is higher in Pax6(+/-) mice. If increased corneal epithelial cell loss exceeds the cell production capacity it could cause corneal homeostasis to become unstable, resulting in progressive corneal deterioration. Although it remains unclear whether Pax6(+/-) mice have LESC-deficiency, we suggest that features of corneal deterioration, that are often taken as evidence of LESC-deficiency, might occur in the absence of stem cell deficiency if corneal homeostasis is destabilised by excessive cell loss.
authors: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Panagiotis
authors: P
authors: Douvaras
authors: Richard L
authors: RL
authors: Mort
authors: Dominic
authors: D
authors: Edwards
authors: Kanna
authors: K
authors: Ramaesh
authors: Baljean
authors: B
authors: Dhillon
authors: Steven D
authors: SD
authors: Morley
authors: Robert E
authors: RE
authors: Hill
authors: John D
authors: JD
authors: West
mesh_terms: D000818:Animals; D015783:Aniridia / Q000235:genetics* / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000378:metabolism* / Q000473:pathology*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D016850:Limbus Corneae / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009030:Mosaicism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins
references: Cell. 1989 Apr 21;57(2):201-9
references: 2702690
references: Invest Ophthalmol Vis Sci. 1989 Sep;30(9):1962-71
references: 2674050
references: PLoS One. 2011;6(12):e28895
references: 22220198
references: Acta Ophthalmol. 2008 Nov;86(7):708-15
references: 18937825
references: Stem Cell Res. 2012 Jan;8(1):109-19
references: 22099025
references: Genes Dev. 1996 Feb 15;10(4):435-46
references: 8600027
references: J Cell Sci Suppl. 1988;10:45-62
references: 3077942
references: Mech Ageing Dev. 1990 Jul;55(1):69-87
references: 2402168
references: Stem Cells. 2012 Sep;30(9):2032-43
references: 22821715
references: Invest Ophthalmol Vis Sci. 1998 Dec;39(13):2554-61
references: 9856765
references: J Bone Miner Res. 2003 Apr;18(4):696-704
references: 12674330
references: Invest Ophthalmol Vis Sci. 1991 May;32(6):1864-75
references: 2032808
references: Dev Cell. 2007 Feb;12(2):195-206
references: 17276338
references: Cell. 2010 Oct 1;143(1):134-44
references: 20887898
references: J Anat. 2011 Sep;219(3):418-37
references: 21615733
references: Ophthalmology. 1995 Oct;102(10):1476-85
references: 9097795
references: Am J Ophthalmol. 1995 Sep;120(3):368-75
references: 7661209
references: Surv Ophthalmol. 1984 May-Jun;28(6):621-42
references: 6330922
references: Cell. 2005 Jul 1;121(7):1109-21
references: 15989959
references: J Embryol Exp Morphol. 1986 Feb;91:197-208
references: 3711786
references: Invest Ophthalmol Vis Sci. 2005 Jan;46(1):126-32
references: 15623764
references: Dev Growth Differ. 1997 Jun;39(3):305-17
references: 9227897
references: Nat Genet. 1993 Feb;3(2):170-4
references: 8499950
references: Invest Ophthalmol Vis Sci. 1996 Aug;37(9):1815-25
references: 8759349
references: Invest Ophthalmol Vis Sci. 1995 Jan;36(1):236-46
references: 7822151
references: Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1775-88
references: 15161840
references: Nature. 1971 Feb 19;229(5286):560-1
references: 4925352
references: J Pathol. 2008 Aug;215(4):421-30
references: 18491289
references: Invest Ophthalmol Vis Sci. 2006 May;47(5):1911-7
references: 16638998
references: EMBO Rep. 2011 Feb;12(2):113-22
references: 21252944
references: Arch Ophthalmol. 1960 Oct;64:536-9
references: 13711262
references: Cornea. 2000 May;19(3):378-83
references: 10832703
references: Stem Cells. 2006 Jun;24(6):1529-38
references: 16456137
references: Results Probl Cell Differ. 2012;55:357-94
references: 22918816
references: Cornea. 1994 Nov;13(6):487-92
references: 7842705
references: Invest Ophthalmol Vis Sci. 2003 May;44(5):1871-8
references: 12714618
references: Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;58(3):229-34
references: 1970685
references: Exp Eye Res. 1999 Mar;68(3):295-301
references: 10079137
references: Stem Cells. 2006 Apr;24(4):1075-86
references: 16282441
references: Cell. 1991 Dec 20;67(6):1059-74
references: 1684738
references: Dev Dyn. 2002 Aug;224(4):432-40
references: 12203735
references: Stem Cells. 2008 May;26(5):1366-75
references: 18276802
references: Am J Ophthalmol. 1979 Apr;87(4):497-502
references: 375739
references: J Anat. 2009 Dec;215(6):698-704
references: 19840025
references: Eur J Hum Genet. 2003 Feb;11(2):163-9
references: 12634864
references: Development. 2011 Aug;138(15):3103-11
references: 21750026
references: Exp Eye Res. 2005 Aug;81(2):224-35
references: 16080917
references: Curr Eye Res. 1993 Nov;12(11):963-74
references: 7508359
references: Dev Dyn. 2004 Jul;230(3):518-28
references: 15188436
references: Nature. 2008 Nov 13;456(7219):250-4
references: 18830243
references: BMC Dev Biol. 2009 Jan 07;9:4
references: 19128502
references: J Cell Sci. 1998 Oct;111 ( Pt 19):2867-75
references: 9730979
references: Biol Cell. 2005 Apr;97(4):265-76
references: 15762848
references: J Pathol. 2008 Jan;214(1):114-22
references: 18027901
references: Science. 2004 May 28;304(5675):1338-40
references: 15060285
references: Invest Ophthalmol Vis Sci. 1990 Oct;31(10):1957-62
references: 2210991
references: Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1415-23
references: 19933176
references: Jpn J Ophthalmol. 2003 Mar-Apr;47(2):119-28
references: 12738543
references: Mol Vis. 2008;14:1929-39
references: 18958303
references: Science. 2010 Nov 5;330(6005):822-5
references: 20929733
references: Nature. 2013 Mar 7;495(7439):65-9
references: 23446353
references: Acta Ophthalmol (Copenh). 1989 Feb;67(1):91-6
references: 2773642
references: PLoS One. 2009 Aug 21;4(8):e6712
references: 19696933
references: Invest Ophthalmol Vis Sci. 1996 Dec;37(13):2572-84
references: 8977471
references: Invest Ophthalmol Vis Sci. 1981 Sep;21(3):434-41
references: 7024181
references: Invest Ophthalmol Vis Sci. 2003 Feb;44(2):558-66
references: 12556383
references: J Cell Biol. 1967 Mar;32(3):677-83
references: 6034484
references: Invest Ophthalmol Vis Sci. 1983 Oct;24(10):1442-3
references: 6618809
references: Biochem Biophys Res Commun. 2009 Jan 16;378(3):539-44
references: 19056354
references: Am J Hum Genet. 1994 May;54(5):801-11
references: 7909985
references: Invest Ophthalmol Vis Sci. 2006 Nov;47(11):4780-6
references: 17065488
references: Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5276-82
references: 17122113
references: J Histochem Cytochem. 2009 Feb;57(2):177-85
references: 19001638
references: Nature. 2012 Apr 15;484(7395):542-5
references: 22504180
references: Science. 2010 Jan 29;327(5965):542-5
references: 20110496
references: Invest Ophthalmol Vis Sci. 1985 Sep;26(9):1296-9
references: 4030257
references: Hum Mol Genet. 1993 Jul;2(7):915-20
references: 8364574
references: J Cell Sci. 2003 Jun 1;116(Pt 11):2157-67
references: 12692153
references: Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1101-8
references: 15037575