Bishop C E, Whitworth D J, Qin Y, Agoulnik A I, Agoulnik I U, Harrison W R, Behringer R R, Overbeek P A
Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas, USA.
Nat Genet. 2000 Dec;26(4):490-4. doi: 10.1038/82652.
In most mammals, male development is triggered by the transient expression of the Y-chromosome gene, Sry, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Several genes, in particular Sox9, have a crucial role in this pathway. Despite this, the direct downstream targets of Sry and the nature of the pathway itself remain to be clearly established. We report here a new dominant insertional mutation, Odsex (Ods), in which XX mice carrying a 150-kb deletion (approximately 1 Mb upstream of Sox9) develop as sterile XX males lacking Sry. During embryogenesis, wild-type XX fetal gonads downregulate Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulate and maintain its expression. We propose that Ods has removed a long-range, gonad-specific regulatory element that mediates the repression of Sox9 expression in XX fetal gonads. This repression would normally be antagonized by Sry protein in XY embryos. Our data are consistent with Sox9 being a direct downstream target of Sry and provide genetic evidence to support a general repressor model of sex determination in mammals.
在大多数哺乳动物中,雄性发育由Y染色体基因Sry的短暂表达触发,该基因启动一系列基因相互作用,最终导致原始胎儿性腺发育为睾丸。几个基因,特别是Sox9,在这一途径中起关键作用。尽管如此,Sry的直接下游靶点以及该途径本身的性质仍有待明确确定。我们在此报告一种新的显性插入突变,Odsex(Ods),携带150 kb缺失(Sox9上游约1 Mb)的XX小鼠发育为缺乏Sry的不育XX雄性。在胚胎发生过程中,野生型XX胎儿性腺下调Sox9表达,而XY和XX Ods/+胎儿性腺上调并维持其表达。我们认为,Ods消除了一个远距离、性腺特异性调控元件,该元件介导XX胎儿性腺中Sox9表达的抑制。这种抑制通常会被XY胚胎中的Sry蛋白拮抗。我们的数据与Sox9是Sry的直接下游靶点一致,并提供了遗传证据来支持哺乳动物性别决定的一般抑制模型。