Cryptic second exon of mouse Sry is essential for male sex determination
A group of researchers from Osaka University identified a cryptic second exon of mouse Sry and a corresponding two-exon type Sry (Sry-T) transcript, clarifying that this cryptic second exon is the real sex determining factor and encodes SRY-T, a world first.
(SRY: the sex determining region on the Y in humans; Sry: the sex determining region on the Y in the mouse)
Since Koopman and other researchers found that Sex-determining region Y protein (SRY) on the Y chromosome is a sex determining gene in 1991, it had been believed that Sry is a single-exon gene on the human Y chromosome and encodes the SRY protein.
In this study, the researchers conducted single-cell transcriptome* analysis of the structure of Sry in mice in their sex-determining stage and found that there is a second exon that encodes two-exon type Sry (Sry-T) as a sex determination factor.
(*Transcriptome analysis is the study of the transcriptome of the complete set of RNA transcripts produced by the genome.)
XY mice lacking Sry-T were sex-reversed and ectopic expression of Sry-T in XX mice induced male development. The researchers edited the endogenous Sry gene to create mice expressing SRY-S with C-terminal mutations on a Sry-T–deficient background and found that these mice developed as male. Their findings suggest that SRY-T is the bona fide testis-determining factor.
In addition, they examined the amino acid sequences of SRY-S and SRY-T and found that the SRY-S carboxyl terminus (C terminus) contains a protein degradation motif (or degron), which is an amino acid sequence that encodes a protein degradation. When the researchers created mice in which the valine in the sequence substituted with another amino acid on a Sry-T–deficient background, degron activity was abolished and the mice developed as males.
They also found that the C terminus of SRY-T encoded in the Sry exon2 was degron free, thereby conferring protein stability on SRY-T. (SRY-S contains a degron, which prevented the SRY-S protein from accumulating to a level required for activating the male pathway.)
It is thought that the Y chromosome that contains Sry loses its ancestral genes over the course of sex chromosome evolution. The degron sequence in the SRY-S C terminus is also thought to cause the loss of gene function. Sry exson2 is composed of retrotransposon-derived sequences, which means that, the degron sequence was prevented through exonization (or creation of new exons) of distal retrotransposon (RNA transposon or virus)-derived sequences. It is thought that in mice, this led to the production of stabilized SRY-T, avoiding the extinction of species.
This group revealed that the SRY-T is the bona fide testis-determining factor. Their achievements will lead to the clarification of the mammal sex determination mechanisms and understanding of how the sex-determining cascade is activated in mammals.
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The article, “The mouse Sry locus harbors a cryptic exon that is essential for male sex determination,” was published in Science at DOI: 10.1126/science.abb6430.
Related links
- Laboratory of Epigenome Dynamics, Graduate School of Frontier Biosciences, Osaka University (link in Japanese)
- Sex Determining Genes that Play a Role in Sex Chromosome Evolution (link in Japanese)
