title: Regulation of gene expression by Pax6 in ocular cells: a case of tissue-preferred expression of crystallins in lens.
abstract: Lens development is an excellent model for genetic and biochemical studies of embryonic induction, cell cycle regulation, cellular differentiation and signal transduction. Differentiation of lens is characterized by lens-preferred expression and accumulation of water-soluble proteins, crystallins. Crystallins are required for light transparency, refraction and maintenance of lens integrity. Here, we review mechanisms of lens-preferred expression of crystallin genes by employing synergism between developmentally regulated DNA-binding transcription factors: Pax6, c-Maf, MafA/L-Maf, MafB, NRL, Sox2, Sox1, RARbeta/RXRbeta, RORalpha, Prox1, Six3, gammaFBP-B and HSF2. These factors are differentially expressed in lens precursor cells, lens epithelium and primary and secondary lens fibers. They exert their function in combination with ubiquitously expressed factors (e.g. AP-1, CREB, pRb, TFIID and USF) and co-activators/chromatin remodeling proteins (e.g. ASC-2 and CBP/p300). A special function belongs to Pax6, a paired domain and homeodomain-containing protein, which is essential for lens formation. Pax6 is expressed in lens progenitor cells before the onset of crystallin expression and it serves as an important regulatory factor required for expression of c-Maf, MafA/L-Maf, Six3, Prox1 and retinoic acid signaling both in lens precursor cells and the developing lens. The roles of these factors are illustrated by promoter studies of mouse alphaA-, alphaB-, gammaF- and guinea pig zeta-crystallins. Pax6 forms functional complexes with a number of transcription factors including the retinoblastoma protein, pRb, MafA, Mitf and Sox2. We present novel data showing that pRb antagonizes Pax6-mediated activation of the alphaA-crystallin promoter likely by inhibiting binding of Pax6 to DNA.
authors.affiliation: The Department of Ophthalmology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. cvekl@aecom.yu.edu
authors.forename: Ales
authors.initials: A
authors.lastname: Cvekl
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Bharesh K
authors.initials: BK
authors.lastname: Chauhan
authors.forename: Kveta
authors.initials: K
authors.lastname: Cveklova
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D003459:Crystallins / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D005123:Eye / Q000196:embryology*; D005136:Eye Proteins / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007908:Lens, Crystalline / Q000196:embryology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D002843:Chromatin; D003459:Crystallins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D004247:DNA