Mutations in the testis-specific enhancer of SOX9 in the SRY independent sex-determining mechanism in the genus Tokudaia.
Mutations in the testis-specific enhancer of SOX9 in the SRY independent sex-determining mechanism in the genus Tokudaia.
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DOI：
10.1371/journal.pone.0108779
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kuroiwa A
中科院分区：
文献类型：
--
作者：
Kimura R;Murata C;Kuroki Y;Kuroiwa A
SRY（sex-determining region Y）是真兽目哺乳动物中广泛保守的一个性别决定基因，位于Y染色体上。SRY蛋白与SF 1结合到SOX 9的睾丸特异性增强子（TES）上，以上调人和小鼠XY胚胎未分化性腺中SOX 9的表达。TES内的核心区域，命名为TESCO，是哺乳动物性别决定的重要增强子。我们发现，TESCO属Tokudaia失去了增强子活性的突变引起的SRY和SF 1结合位点。两种Tokudaia不具有Y染色体或SRY，并且一种具有位于由Y与常染色体融合的neo-Y染色体上的多个SRY。Tokudaia TESCO的序列与小鼠TESCO的序列具有83%以上的同源性，但是在3个SRY结合位点中的2个和6个SF 1结合位点中的5个中发现了核苷酸替换。在报告基因测定中，所有物种的TESCO在用SRY和SF 1以及SOX 9和SF 1共转染的细胞中显示出低增强子活性。突变的TESCO，其中在SRY和SF 1结合位点中发现的核苷酸取代被小鼠序列取代，恢复了活性。此外，SRY阳性物种的SRY不能激活突变的TESCO或小鼠TESCO，表明SRY不再作为性别决定基因发挥作用。我们的研究结果表明，SRY依赖的性别决定机制在Tokudaia属的一个共同祖先中丢失，这是由于SRY和SF 1结合位点的核苷酸取代后出现了一个新的性别决定基因。我们首次证明了在哺乳动物性别决定机制的进化过程中存在一个从SRY到一个新的性别决定基因的过渡阶段。
SRY (sex-determining region Y) is widely conserved in eutherian mammals as a sex-determining gene located on the Y chromosome. SRY proteins bind to the testis-specific enhancer of SOX9 (TES) with SF1 to upregulate SOX9 expression in undifferentiated gonads of XY embryos of humans and mice. The core region within TES, named TESCO, is an important enhancer for mammalian sex determination. We show that TESCO of the genus Tokudaia lost enhancer activity caused by mutations in its SRY and SF1 binding sites. Two species of Tokudaia do not have the Y chromosome or SRY, and one species has multiple SRYs located on the neo-Y chromosome consisting of the Y fused with an autosome. The sequence of Tokudaia TESCO exhibited more than 83% identity with mouse TESCO, however, nucleotide substitution(s) were found in two out of three SRY binding sites and in five out of six SF1 binding sites. TESCO of all species showed low enhancer activity in cells co-transfected with SRY and SF1, and SOX9 and SF1 in reporter gene assays. Mutated TESCO, in which nucleotide substitutions found in SRY and SF1 binding sites were replaced with mouse sequence, recovered the activity. Furthermore, SRYs of the SRY-positive species could not activate the mutated TESCO or mouse TESCO, suggesting that SRYs lost function as a sex-determining gene any more. Our results indicate that the SRY dependent sex-determining mechanism was lost in a common ancestor of the genus Tokudaia caused by nucleotide substitutions in SRY and SF1 binding sites after emergence of a new sex-determining gene. We present the first evidence for an intermediate stage of the switchover from SRY to a new sex-determining gene in the evolution of mammalian sex-determining mechanism.
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