title: Transcription Factor PAX6 (Paired Box 6) Controls Limbal Stem Cell Lineage in Development and Disease.
abstract: PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. Defects in Pax6 cause aniridia and LSC deficiency in humans and the Sey (Small eye) phenotype in mice (Massé, K., Bhamra, S., Eason, R., Dale, N., and Jones, E. A. (2007) Nature 449, 1058-1062). However, how PAX6 specifies LSC and corneal fates during eye development is not well understood. Here, we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, p63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors and later in LSCs. Using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs led to up-regulation of skin epidermis-specific keratins concomitant with differentiation to a skin fate. Using gene expression analysis, we identified the involvement of Notch, Wnt, and TGF-β signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in the keratin gene expression profile and by the appearance of congenital dermoid tissue.
authors.affiliation: From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Gen
authors.initials: G
authors.lastname: Li
authors.affiliation: the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Xu
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Michal
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: the Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Sherrinal
authors.initials: S
authors.lastname: Patel
authors.affiliation: the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China, Guangzhou KangRui Biological Pharmaceutical Technology Company Limited, Guangzhou 510005, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Cai
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chen
authors.affiliation: From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Meixia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China, the Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Guiqun
authors.initials: G
authors.lastname: Cao
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Emily
authors.initials: E
authors.lastname: Yeh
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Danni
authors.initials: D
authors.lastname: Lin
authors.affiliation: the Laboratory Animal Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China, and.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Su
authors.affiliation: the Laboratory Animal Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China, and.
authors.forename: Wen-wen
authors.initials: WW
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Medicine, and.
authors.forename: George L
authors.initials: GL
authors.lastname: Sen
authors.affiliation: the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Natalie
authors.initials: N
authors.lastname: Afshari
authors.affiliation: Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093-0838.
authors.forename: Shaochen
authors.initials: S
authors.lastname: Chen
authors.affiliation: the Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
authors.affiliation: Department of Cellular and Molecular Medicine, and.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China, the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China, the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, Department of Cellular and Molecular Medicine, and Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093-0838, the Veterans Administration Healthcare System, San Diego, California 92161 kang.zhang@gmail.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China, the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
authors.forename: Hong
authors.initials: H
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000502:physiology*; D003315:Cornea / Q000196:embryology; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008032:Limbic System / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: C081876:CKAP4 protein, human; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins
keywords: cell differentiation; cornea; eye; stem cells; transcription factor