Format

Send to

Choose Destination
J Biol Chem. 2015 Aug 14;290(33):20448-54. doi: 10.1074/jbc.M115.662940. Epub 2015 Jun 4.

Transcription Factor PAX6 (Paired Box 6) Controls Limbal Stem Cell Lineage in Development and Disease.

Author information

1
From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China.
2
the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
3
the Department of Ophthalmology, Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine.
4
the Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
5
From the Molecular Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China, Guangzhou KangRui Biological Pharmaceutical Technology Company Limited, Guangzhou 510005, China.
6
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.
7
the Laboratory Animal Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China, and.
8
Department of Cellular and Molecular Medicine, and.
9
Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093-0838.
10
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.
11
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.

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.

KEYWORDS:

cell differentiation; cornea; eye; stem cells; transcription factor

PMID:
26045558
PMCID:
PMC4536450
DOI:
10.1074/jbc.M115.662940
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center