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Scientists have identified a key enhancer of Sox9- a gene critical for male sex development and demonstrated that deleting that non-coding DNA results in male-to-female sex reversal in mice. The findings could have important implications for patients with differences in sex development (DSDs), in which reproductive organs don’t develop as expected.
The study was a collaboration between the laboratories of the late Danielle Maatouk, PhD, assistant professor of Obstetrics and Gynecology at Northwestern University Feinberg School of Medicine and corresponding author Robin Lovell-Badge, PhD, of the Francis Crick Institute in London.
Maatouk’s research focused on sex determination, the process during which embryos develop either testes or ovaries. Her laboratory focused on exploring how non-coding elements-parts of DNA that don’t encode for proteins regulate gene expression and impact this process.
The Sox9 gene is crucial for male differentiation and the proper formation of testes; if Sox9 is mutated or incorrectly expressed, an individual who is chromosomally male (XY) can develop ovaries instead of testes. Previously, it was known that some patients with DSDs have changes in their genome near the Sox9 gene that alter its expression and lead to sex reversal.
In the current study, the scientists identified an enhancer-a short region of DNA that can increase gene transcription that is necessary to regulate expression of the Sox9 gene. When the scientists deleted the enhancer in mouse models, they discovered that Sox9 expression was decreased enough to cause complete sex reversal; mouse embryos that were chromosomally male (XY) developed as phenotypically normal females, with ovaries that were indistinguishable from those of XX females. The findings could improve the genetic diagnosis of patients with DSDs
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