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Sox Genes: Architects of Development

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Sox Genes: Architects of Development SOX GENES: ARCHITECTS OF DEVELOPMENT Heather M. Prior and Michael A. Walter Ocular Genetics Research Group, University of Alberta, Edmonton, Alberta, Canada Development in higher organisms involves com- scription factors have a distinct activation domain plex genetic regulation at the molecular level. which interacts with other proteins to coordinately The emerging picture of development control control gene transcription. A simplified model of includes several families of master regulatory the regulation of downstream target genes by genes which can affect the expression of down- transcription factors is shown in Fig. 1. stream target genes in developmental cascade Large "families" of transcription factors pathways. One new family of such development which are involved in the control of develop- regulators is the SOX gene family. The SOX mental pathways have been identified. These genes are named for a shared motif called the gene families encode proteins characterized by 5RY box, a region homologous to the DNA-bind- well-defined DNA-binding motifs, such as zinc- ing domain of SRY, the mammalian sex deter- fingers or homeobox domains, typically highly mining gene. Like SRY, SOX genes play impor- conserved across species (3,4). Many of these tant roles in chordate development. At least a genes were first studied in Drosophila. An exam- dozen human SOX genes have been identified ple is the HOM/HOX (hQmeobQx-containing) and partially characterized (Tables 1 and 2). Mu- gene complexes which play a role in early pat- tations in SOX9 have recently been linked to tern formation in the Drosophila larva and have campomelic dysplasia and autosomal sex rever- also been implicated in pattern formation in sal, and other SOX genes may also be associated early vertebrate development (5). Within the with human disease. PAX (paired box) family of genes (6), PAX6 is a master eye development control gene in organ- isms as diverse as insects, cephalopods, and hu- mans. Interestingly, mutations in this gene cause either aniridia or autosomal dominant keratitis, two congenital eye defects in humans (7-9). Mu- OVERVIEW: DEVELOPMENT tations in other PAX genes also cause human diseases, including coloboma and renal anoma- CONTROL BY ARCHITECTURAL lies (PAX2), and Waardenburg syndrome (PAX3) TRANSCRIPTION FACTORS (10,11). While SOX genes have not yet been as The process of development includes the increas- well characterized, they appear to also play im- ing differentiation of pluripotent progenitor cells. portant roles in early development and to have Since the pattern of transcribed proteins within interesting associations to human disease. each cell ultimately determines its identity in the The SOX genes belong to a large group of context of tissue, organ, and organism, the reg- genes in which the DNA-binding domain is ulation of transcription is at the foundation of called a high mobility group (HMG) box (12). any development control pathway. Two basic types of HMG-class proteins can be Basic gene transcription is regulated by tran- delineated. One group is characterized by pro- scription factors, proteins which bind specific teins containing multiple HMG boxes, having a DNA sequences called promoters or enhancers general affinity for binding DNA independent of located within and around the gene (1,2). In its sequence. This group includes the HMG- 1 addition to a DNA-binding domain, most tran- protein, ubiquitous binding factor (UBF), and mitochondrial transcription factor 1 (MT-TF1). Address correspondence and reprint requests to: Michael A. The second category of HMG-class proteins con- Walter, Ocular Genetics Laboratory, 671 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, sists of those with a single HMG box and that T6G 2S2, Canada. bind DNA in a highly sequence-specific manner. Copyright 1996, Molecular Medicine, 1076-1551/96/$10.50/0 405 Molecular Medicine, Volume 2, Number 4, July 1996 405-412 406 Molecular Medicine, Volume 2, Number 4, July 1996 TABLE 1. Accession numbers of human and factor-I (LEF-1) (13,14), as well as the SOX and mouse Sox sequences SRY genes. Genes in this category share about 25% sequence identity over the 79 amino acid Accession Sequence HMG box, with little or no similarity outside this Number Data box. It has been directly demonstrated for SRY, SOX4, and SOX5 (15-17) that these proteins Human Gene bind in the minor groove of DNA at the consen- SRY L08063 Complete sus sequence A/T A/T C A A A G. The binding L10102 induces a sharp bend of 800 to 1350 in the DNA LIOIOI template (18,19), which in turn may act to bring X53772 different regulatory regions of the target gene into SOX2 Z31560 Partial close proximity. As a result, various transcription SOX3 X71135 Complete factors bound to these regions would be able to SOX4 X70683 Complete interact to activate transcription. DNA-binding pro- SOX5 X65662 HMG box teins with this "structural" mode of action have been appropriately called architectural transcrip- SOX6 X65663 HMG box tion factors (20). SOX8 X65664 HMG box SOX9 Z46629 Complete S74504-S74506 Soxi1 X65666 HMG box SOXll X73038 HMG box THE SRY GENE AND SEX SOX12 X73039 HMG box DETERMINATION Mouse Gene The first SOX gene to be successfully cloned and Sry X55491 Complete characterized was the SRY gene (Fig. 2), and it SoxI X94126 Complete remains the defining member of the family (22). Sox2 X94127 Complete The critical region on the Y chromosome was U31967 initially established by molecular analysis of the DNA of sex reversed patients, including XX Sox3 X94125 Complete males with portions of the Y chromosome trans- Sox4 X70298 Complete located to one of the X chromosomes and XY Sox5 X65657 Complete females with deletions within the Y chromo- S45834 some. Although a number of candidate genes Sox6 U32614 Complete initially looked promising, SRY was shown in Sox7 X65660 HMG box 1990 to be the one necessary for male sex deter- Sox8 Z18957 HMG box mination since mutations within its open reading Sox9 Z18958 HMG box frame were found in XY sex reversed patients SoxlO Z18959 HMG box (23,24). All the mutations identified fell within Sox 1I Z18960 HMG box the HMG box region of the SRY gene. Subse- Soxl2 Z18961 HMG box quent experiments showing that XX transgenic Soxl3 Z18962 HMG box mice carrying the SRY gene were phenotypically male (25) demonstrated that this gene was suf- Soxl4 Z18963 HMG box ficient for male sex determination. Soxl5 X70909 HMG box In male mice, the SRY protein is expressed in Soxl6 L29084 HMG box the bipotential genital ridge of the developing Soxl7 L29085 HMG box embryo (26). Outside the genital ridge, SRY Soxl8 L35032 Complete mRNA levels are regulated by an unusual trans- lational control system whereby a unique splic- ing event produces non-functional circular tran- scripts (27). The gonad in the absence of SRY develops, by default, as an ovary. During male Some members of this group are proteins en- development, SRY acts to induce MIS (Miillerian coded by the yeast mating type genes matMc and inhibiting substance) expression, which in turn mat-Al, the white cell regulatory genes T cell causes regression of the Miillerian duct system factor-i (TCF- 1) and the lymphocyte enhancer (female), progression of the Wolffian ducts Minireview 407 TABLE 2. SOX genes Sequence Chromosome Data Disease Group Gene (Human) (Human)a Association Tissue A SRY Y + XY sex reversal Genital ridge B SOXi SOX2 3q26.3-27 + Embryo CNS SOX3 Xq26.2-27.2 + Borjeson-Forssman-Lehmann (?) Embryo CNS SOX14 SOX15 SOX19 C SOX4 6p + Lymphocytes Soxil + Embryo CNS SOX12 + SOX20 17pl3 + D SOX5 + Adult testis SOX6 + Testis, embryo CNS SOX13 E SOX8 + SOX9 17q24 + Campomelic dysplasia, sex reversal Adult testis Sox1o + F SOX7 SOX17 SOX18 Muscle aComplete human cDNA sequence data for SRY, SOX3, SCX4, and SCX9 only. (male), and gonadal development as testis (28). brates, including mouse, chicken, gull, frog, turtle, The SRY product may also act to induce male zebrafish, marsupials, and humans (12,29-35). steroidogenesis, which in turn leads to male ex- Although the majority of work has concen- ternal genitalia. Affinity studies to determine the trated on the mouse Sox genes, several human precise downstream targets of SRY have shown that it probably binds to intervening intermedi- ate factors in both the MIS and the male steroi- ^ Development dogenesis pathways (28). conro gone _ DN4Abing pro-dn ponfactor) SOX GENES _ of from The SOX (SRY-related HMG box) genes were ~ loAdvan tripdon results binding oft_renepfon actr initially identified through their homology to the HMG box of SRY. By definition, the DNA-bind- Twget gene ing domain of SOX genes is at least 60% similar Promotr I enhacer region or 50% identical to the 79 amino acid HMG box FIG. 1. Downstream regulation model of the SRY gene. At least 19 SOX genes have been identified and divided into six groups, des- Development control genes encode transcription fac- tors with DNA-binding domains. These factors bind ignated A-F (Table 2), according to the similari- to the promoter/enhancer regions of target genes ties of their HMG box regions (Fig. 3). SOX genes and often interact with other proteins to influence have been found in Drosophila and many verte- transcription levels in the target genes. 408 Molecular Medicine, Volume 2, Number 4, July 1996 93 263 500 706 840bp recent study implicates chicken Sox2 in the lens- ATG polyA specific regulation of the 61-crystallin gene (43). 4*-- 204amnoadlds - Human SOX2 has been partially cloned and mapped to chromosome 3q26.3-27 (44). In ad- FIG. 2. Structure of the SRY gene dition, murine Sox2 has been found to complex The SRY gene has a single open reading frame another transcription factor, Oct-3, to pro- 79-amino acid HMG box (21).
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