https://www.cell.com/cell/pdf/0092-8674(93)90279-Y.pdf

Circular transcripts of the testis-determining gene Sry in adult mouse testis

The pivotal point of vertebrate sex determination is the development of the gonad into a testis or ovary, which governs phenotypic sex through the production of hormones. The identification of Sry, the genetic switch that controls testis development in mammals, fuelled the race for the discovery of downstream pathways. Comparative analyses of XY versus XX gonadogenesis in both mouse and human genetic mutants have uncovered a burgeoning network of intra- and extra-cellular pathways. Here, we review the old and new players that are involved in the initial steps of testis and ovary development.

One tissue, two fates: molecular genetic events that underlie testis versus ovary development.

Molecular basis of human 46X,Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex.

The protein encoded by the human testis determining gene, SRY, contains a high mobility group (HMG) box related to that present in the T cell-specific, DNA-binding protein TCF-1. Recombinant SRY protein was able to bind to the same core sequence AACAAAG recognized by TCF-1 in a sequence dependent manner. In five XY females point mutations were found in the region encoding the HMG box. In four cases DNA binding activity of mutant SRY protein was negligible; in the fifth case DNA binding was reduced. These results imply that the DNA binding activity of SRY is required for sex determination.

DNA binding activity of recombinant SRY from normal males and XY females

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 CLONING OF SRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 EQUIVALENCE OF SRY AND TDF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 SRY IN OTHER SPECIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 THE TRANSCRIPTION UNIT OF HUMAN AND MOUSE SRY GENES . . . . . . 80 BIOCHEMISTRY AND MODE OF ACTION OF SRY . . . .. . . . . . . . . . . . . . 82 GENES THAT INTERACT WITH SRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 SRY ACTION AND CELL·CELL INTERACTIONS . . .. . . . . . . . . . . . . . . . . 85 GENES RELATED TO SRY: THE SOX GENES . . . . . . . . . . . . . . . . . . . . . . 87 CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

SRY and Sex Determination in Mammals

XY females (n=17) were analysed for mutations in SRY (sex-determining region Y gene), a gene that has recently been equated with the testis determining factor (TDF). SRY sequences were amplified by the polymerase chain reaction (PCR) and analysed by both the single strand conformational polymorphism assay (SSCP) and DNA sequencing. The DNA from two individuals gave altered SSCP patterns; only these two individuals showed any DNA sequence variation. In both cases, a single base change was found, one altering a tryptophan codon to a stop codon, the other causing a glycine to arginine amino acid substitution. These substitutions lie in the high mobility group (HMG)-related box of the SRY protein, a potential DNA-binding domain. The corresponding regions of DNA from the father of one individual and the paternal uncle of the other, were sequenced and found to be normal. Thus, in both cases, sex reversal is associated with de novo mutations in SRY. Combining this data with two previously published reports, a total of 40 XY females have now been analysed for mutations in SRY. The number of de novo mutations in SRY is now doubled to four, adding further strength to the argument that SRY is TDF.

J. Levilliers

Papers

Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal