Insulin and insulin-like growth factors (IGFs) are hormones known for their role in metabolism and growth, but now scientists are elucidating their importance in another arena: sex determination. Researchers at the University of Geneva (UNIGE) found that in the absence of these factors at the time of sex determination, embryos do not differentiate into either male or female and have no adrenal glands.
In mammals, the sperm’s transmission of an X or Y sex chromosome determines the genetic sex of the embryo, but the following developmental stages translate this genetic sex into gonadal sex, that is, either ovaries or testes. The researchers set out to better understand the first stages of sexual development.
The team was interested in the role of IGFs and their receptors in cells. Though it is now recognized that the interactions between metabolism, growth, and reproductive capacity are regulated by common factors such as insulin and IGFs, this study shows that these interactions are even more important than previously believed because the insulin and IGF receptors are also essential for primary sex determination in mammals.
To analyze the impact of these hormones on sex determination, the group used genetically modified mice. The scientists genetically inactivated the receptors for insulin and IGFs in mouse embryos. This led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination, together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. As such, the embryo and its gonads remained stuck in a fully undifferentiated state for several days.
The authors explain that embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that mutant gonads, regardless of genetic sex, remained in an extended undifferentiated state before the ovarian differentiation program ultimately is initiated at around embryonic day 16.5. These findings demonstrated the essential role of these hormones and growth factors in sexual differentiation, the authors report.
“This study provides a better understanding of the basic mechanisms of sexual development and is a step forward toward a better understanding of the causes of sexual ambiguities, which often remain unknown,” states Serge Nef, professor at the department of genetic medicine and development at UNIGE. “The research we are conducting will provide the opportunity to refine and improve clinical diagnosis of individuals with disorders of sex development.”
The study was published yesterday in PLOS Genetics, in an article titled “Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice”.