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An Everted Repeat Mediates Retinoic Acid Induction of the 7F-Crystallin Gene: Evidence of a Direct Role for Retinoids in Lens Development

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An Everted Repeat Mediates Retinoic Acid Induction of the 7F-Crystallin Gene: Evidence of a Direct Role for Retinoids in Lens Development Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press An everted repeat mediates retinoic acid induction of the 7F-crystallin gene: evidence of a direct role for retinoids in lens development Mark Tini, 1"2 Gail Otulakowski, 1'3 Martin L. Breitman, 2'4 Lap-Chee Tsui, 2,s and Vincent Gigu~re 1'2"6 tDivision of Endocrinology and SGenetics, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; 2Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; 4Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5S 1A8, Canada. The vertebrate lens is a classical system for examining mechanisms of tissue determination and differentiation, yet little is known about the signaling molecules controlling its development. Here, we report that retinoic acid IRA}, a substance known for its teratogenic effects on the eye and as a natural endogenous morphogenetic agent, acts as a regulator of gene expression in the lens. We have identified a novel type of RA response element (RARE) within the lens-specific mouse 7F-crystallin promoter, consisting of two (A/G)GGTCA motifs in an everted arrangement spaced by 8 nucleotides. This element {TF-RARE) mediates activation of the 7F-crystallin promoter by ligand-activated endogenous lens cell RA receptors (RARs) and confers RA responsiveness when linked to a heterologous promoter. 7F-RARE is bound in vitro by RAR/RXR heterodimers, and both receptors cooperate in vivo to trans-activate this element. These observations demonstrate a direct effect of RA on lens-specific gene expression and reveal a novel role for retinoids in the development and homeostasis of the mammalian eye. [Key Words: Retinoic acid; lens; eye; mouse; crystallin; nuclear receptor] Received October 15, 1992; revised version accepted December 8, 1992. The ocular lens is an encapsulated transparent tissue thelial cells differentiate into fiber cells in response to that performs a critical role in vision by focusing light factors secreted from the retina (Coulombre and Cou o onto the retina, where photoreceptors transduce the lombre 1963; Yamamoto 1976; Reyer 1977}. Although a light signal. It consists of a layer of mitotically active number of hormones and growth factors have been epithelial cells at the anterior surface and differentiated shown to influence growth and differentiation of lens fiber cells in the remainder of the lens. The transparent cells in culture (Piatigorsky 1973; Beebe et al. 1987; and refractive properties of the lens are dependent on the Chamberlain and McAvoy 1987; Brewitt and Clark ordered packing of a number of abundant proteins re- 1988}, it is not known what signals are required in vivo. ferred to as crystallins (Delaye and Tardieu 1983}. In Thus, the 7-crystallin genes provide an excellent oppor- mammals, there are three major classes of crystallins (c~, tunity to investigate the molecules and mechanisms 6, and ~/), which are temporally and spatially differen- that regulate differentiation during lens development. tially expressed within the lens (McAvoy 1978; Van Leen It has been known for decades that retinoids, the fam- et al. 1987a; Wistow and Piatigorsky 1988}. In particular, ily of biologically active derivatives of vitamin A, are there are six closely related, chromosomally linked essential for vision. In the retina, 11-cis retinal functions 7-crystallin genes in the murine genome (Lok et al. 1984; as the chromophore component of the photoreceptors, Moormann et al. 1985}, whose expression is differen- and vitamin A deficiency can lead to night blindness and tially regulated and restricted to fiber cells (Murer-Or- eventually causes irreversible ocular dysfunction [Good- lando et al. 1987; Van Leen et al. 1987b; Breitman et al. man 1984}. However, retinoids may play a more compre- 19891. During the final stage of lens development, epi- hensive role in eye physiology. Retinoids regulate devel- opmental processes at various stages of vertebrate em- bryogenesis (Tabin 1991) and exposure of pregnant 3Present address: The R.W. Johnson PharmaceuticalResearch Institute, Don Mills, Ontario, M3C 1L9, Canada. mammals to high levels of retinoic acid (RA) results in a 6Correspondingauthor. wide range of malformations in the fetus including mi- GENES & DEVELOPMENT7:295-307 91993 by Cold Spring HarborLaboratory Press ISSN 0890-9369/93 $3.00 295 Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Tini et al. croopthalmia and anopthalmia (Lammer et al. 1985; Results Rosa et al. 1986). Relatively high levels of RA are syn- Interaction of lens proteins with the TF enhancer thesized in the retina through the oxidation of retinal- dehyde (McCaffery et al. 1992), suggesting that RA may Transfection studies have established that sequences be an important regulator of eye development and ho- -226 to + 47 of the mouse ~/F-crystallin promoter are meostasis. sufficient for maximal promoter activity in chick lens The effects of retinoids on cellular activity result from epithelial cells (Lok et al. 1989). Within this segment the activation of two distinct classes of nuclear recep- two domains have been identified that are necessary for tors, referred to as retinoic acid receptors (RARs) maximal promoter activity: an enhancer element lo- {Giguhre et al. 1987, 1990; Petkovich et al. 1987; Ben- cated between - 226 and - 123 and a proximal lens-spe- brook et al. 1988; Brand et al. 1988; Zelent et al. 1989) cific element (LSE) located immediately upstream of the and retinoid X receptors (RXRs) (Mangelsdorf et al. 1990, TATA box (Fig. 1) (Lok et al. 1989; Liu et al. 1991}. The 1992). RARs and RXRs belong to a subgroup of the su- activity of the enhancer is highly dependent on se- perfamily of steroid and thyroid hormone receptors that quences -226 to -171, as deletion of this segment re- recognizes hormone response elements (HREs) com- sults in a sharp decrease in promoter activity. To further posed of direct repeats of the core half-site motif (A/ increase our understanding of the molecular mecha- G)GGTCA. It has been proposed recently that specificity nisms regulating ~F-crystallin gene expression, we de- of DNA binding and transcriptional activation of these cided to characterize the interaction of endogenous lens receptors is dictated by the spacing between the repeats: proteins with this region by performing electrophoretic HREs with spacers of 3, 4, and 5 bp confer specific re- mobility shift assays (EMSAs) using an enhancer frag- sponse to vitamin D3, thyroid hormone, and RA, respec- ment and chick lens nuclear extracts. A restriction frag- tively (Niiiir et al. 1991; Umesono et al. 1991). The spec- ment encompassing sequences - 226 to - 151 yields two ificity of the retinoid response is further imposed by a major retarded bands that can be competed with pro- series of complex interactions between the two types of moter segment -226 to + 47 [~/F(- 226)] (Fig. 2A, lane 3) receptors and their ligands. RARs respond to both all- but not with a nonspecific segment derived from pUG18 trans RA and 9-cis RA, whereas RXR is activated specif- (Fig. 2A, lane 4). Formation of this complex could also be ically by the 9-cis isomer (Heyman et al. 1992; Levin et prevented by inclusion of 5' flanking sequences - 529 to al. 1992). Furthermore, RARs can bind RA response ele- +33 of the mouse ~A-crystallin gene (Fig. 2A, lane 5). ments (RAREs) and regulate transcription efficiently 5'-Flanking sequences of the ~/F- and ~/A-crystallin genes only when forming heterodimeric complexes with RXRs display a high degree of sequence identity in the proxi- {Yu et al. 1991; Kliewer et al. 1992a; Leid et al. 1992; mal domain (Fig. 1, sequence -67 to -25) and increas- Zhang et al. 1992a) while RXRs, in the presence of 9-cis ing divergence upstream of this region (Murer-Orlando et RA, can form homodimers that bind a subset of RAREs al. 1987; Lok et al. 1989). The ability of the ~/A-crystallin with high affinity (Zhang et al. 1992b). segment to compete for binding suggests that a similar The demonstration that RAR and RXR function as ret- binding site is located within this promoter. inoid-activated transcription factors suggests that if ret- To further characterize this binding site we used the inoids control lens development, they must activate the methylation interference assay to identify guanine resi- expression of a particular subset of lens specific genes. dues that are in direct contact with nuclear proteins in- As discussed above, lens differentiation is associated teracting with this region. Asymmetrically end-labeled with the synthesis of the structural proteins, ~-crystal- segment -226 to -164 was partially methylated and lins, that serve as molecular markers of lens cell differ- incubated with lens nuclear extracts to identify guanine entiation. Previous characterization of the mouse ~/F- positions which, when methylated, interfere with com- crystallin promoter has established that 5' flanking plex formation. This analysis identified seven guanine sequences -226 to + 47 are sufficient for optimal pro- contacts, located between -207 and - 190, that cluster moter activity in cultured lens epithelial cells (Lok et al. at or near (A/G)GGTCA repeats (Fig. 2B). 1989). This segment contains a proximal element re- To confirm that the major retarded bands observed by sponsible for lens specificity and an enhancer element EMSA with the -226/- 151 fragment represent interac- essential for full activity of the promoter (Lok et al. 1989; Liu et al. 1991). Transgenic studies have also indicated that while sequences - 171 to + 47 are sufficient for lens fiber-specific expression of the lacZ reporter gene, up- stream sequences (-759 to -171) are required for max- imal expression (Goring et al. 1987; Yu et al. 1990). Here, we show that an element composed of an everted repeat of the (A/G)GGTCA motif located within the enhancer Figure 1.
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