Regulation of gene expression by Pax6 in ocular cells: A case of tissue-preferred expression of crystallins in lens

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 developmental regulated DNA-binding transcription factors: Pax6, c-Maf, MafA/L-Maf, MafB, NRL, Sox2, Sox1, RARβ/RXRβ, RORα, Prox1, Sbr3, γFBP-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/crtromatin 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 αA-, α3-, γF- and guinea pig ζ-crystallins. Pax6 forms functional complexes with a number of transcription factors including the retinoblastoma protein, pRb, MafA, Mit1 and Sox2. We present novel data showing that pRb antagonizes PaxG-mediated activation of the αA-crystallin promoter likely by inhibiting binding of Pax6 to DNA.