Abstract
The mammalian gonad is adapted for the production of germ cells and is an endocrine gland that controls sexual maturation and fertility. Gonadal sex reversal, namely, the development of ovaries in an XY individual or testes in an XX, has fascinated biologists for decades. The phenomenon suggests the existence of genetic suppressors of the male and female developmental pathways and molecular genetic studies, particularly in the mouse, have revealed controlled antagonism at the core of mammalian sex determination. Both testis and ovary determination represent design solutions to a number of problems: how to generate cells with the right properties to populate the organ primordium; how to produce distinct organs from an initially bipotential primordium; how to pattern an organ when the expression of key cell fate determinants is initiated only in a discrete region of the primordium and extends to other regions asynchronously; how to coordinate the interaction between distinct cell types in time and space and stabilize the resulting morphology; and how to maintain the differentiated state of the organ throughout the adult period. Some of these, and related problems, are common to organogenesis in general; some are distinctive to gonad development. In this review, we discuss recent studies of the molecular and cellular events underlying testis and ovary development, with an emphasis on the phenomenon of gonadal sex reversal and its causes in mice and humans. Finally, we discuss sex-determining loci and disorders of sex development in humans and the future of research in this important area. WIREs Dev Biol 2012, 1:559–577. doi: 10.1002/wdev.42
Highlights
Sex-Determining Gene Regulatory NetworksGonadal sex reversal is a developmental phenomenon that reveals key features of the sex determination process in mammals
This is achieved through its positive interaction with the secreted molecules fibroblast growth factor 9 (FGF9) and prostaglandin D2 (PGD2)
The requirement that a threshold of SRYpositive cells exist in the XY gonad in order for testis development to proceed, a fact established by analysis of gonad development in XX-XY chimeras, strongly suggests that proliferation of Sertoli cell precursors may be an important component of testis determination
Summary
Gonadal sex reversal is a developmental phenomenon that reveals key features of the sex determination process in mammals. We begin with a brief outline of our current understanding of testis and ovary determination at the molecular and cellular level (see overview in Figures 1 and 2) This framework will be used to focus on particular events in sex determination and flesh out some of the details of why disruption to these can cause sex reversal. Once cellular- and tissue-level thresholds of Sry (and Sox9) expression are met (Box 1), SOX9 protein acts to ‘lockin’ its own expression such that it is subsequently maintained at high levels in the Sertoli cell lineage This is achieved through its positive interaction with the secreted molecules fibroblast growth factor 9 (FGF9) and prostaglandin D2 (PGD2). These molecules are thought to be important in securing two other necessary steps in testis determination: the recruitment of other somatic cells to the Sertoli cell
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