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Mol Cell Biol, April 1998, p. 2067-2076, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Lens-Specific Gene Recruitment of -Crystallin through Pax6, Nrl-Maf, and Brain Suppressor Sites

Ronit Sharon-Friling,^1, Jill Richardson,^1, Sally Sperbeck,¹ Douglas Lee,^1,§ Michael Rauchman,² Richard Maas,² Anand Swaroop,³ and Graeme Wistow^1,*

Section on Molecular Structure and Function, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892¹; Brigham and Women's Hospital, Boston, Massachusetts 02115²; and W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan 48105³

Received 7 August 1997/Returned for modification 26 September 1997/Accepted 23 December 1997

-Crystallin is a taxon-specific crystallin, an enzyme which has undergone direct gene recruitment as a structural component of the guinea pig lens through a Pax6-dependent mechanism. Tissue specificity arises through a combination of effects involving three sites in the lens promoter. The Pax6 site (ZPE) itself shows specificity for an isoform of Pax6 preferentially expressed in lens cells. High-level expression of the promoter requires a second site, identical to an CE2 site or half Maf response element (MARE), adjacent to the Pax6 site. A promoter fragment containing Pax6 and MARE sites gives lens-preferred induction of a heterologous promoter. Complexes binding the MARE in lens nuclear extracts are antigenically related to Nrl, and cotransfection with Nrl elevates -crystallin promoter activity in lens cells. A truncated  promoter containing Nrl-MARE and Pax6 sites has a high level of expression in lens cells in transgenic mice but is also active in the brain. Suppression of the promoter in the brain requires sequences between 498 and 385, and a site in this region forms specific complexes in brain extract. A three-level model for lens-specific Pax6-dependent expression and gene recruitment is suggested: (i) binding of a specific isoform of Pax6; (ii) augmentation of expression through binding of Nrl or a related factor; and (iii) suppression of promoter activity in the central nervous system by an upstream negative element in the brain but not in the lens.

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^* Corresponding author. Mailing address: Section on Molecular Structure and Function, National Eye Institute, Building 6 Room 331, National Institutes of Health, Bethesda, MD 20892-2740. Phone: (301) 402-3452. Fax: (301) 496-0078. E-mail: graeme{at}mge2.nei.nih.gov.

Present address: Columbia University, New York, NY 10027.

Present address: Glaxo R&D, Stevenage SG1 2NY, United Kingdom.

^§ Present address: Bayer Corp., Clayton, NC 27502.

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