146 - Genetics of Sex Determination and Differentiation

Abstract

The classical paradigm of mammalian, including human, sexual development postulates an initially “indifferent” (sexually undifferentiated) state that is transformed, in two major stages, into the sexually dimorphic male and female forms. The two stages are called primary, relating to the gonad, and secondary, referring to all other genital organs. In the first stage, primary sex determination, specific sex-determining genetic factors that are present from conception drive the development of the gonad. In the second stage, secondary sexual differentiation, all other features of sexual dimorphism are established. In this concept, all features of both internal and external sexually dimorphic structures other than the gonads develop from the action of hormones produced in males by the testis, lack of these hormones (or production of other hormones) in females, and independently of the sex-determining gene(s). This paradigm is known as the Jost principle, and has remained largely unchanged since the 1950s. However, recent molecular genetic findings have challenged this view to some extent, revealing a large number of genetic pathways that interact in a complex overlapping and redundant manner to execute the genetic control of sexual development. This chapter reviews the current state of knowledge of sex determination and differentiation, including aspects that both fall within and extend the Jost paradigm, under the following headings:1.Chromosomal assignment of sex2.Pregonadal sexual development and nongonadal sexual dimorphism3.Formation and development of the indifferent gonad4.Transformation of the indifferent gonad into a testis or an ovary5.Lifelong maintenance of gonadal identity6.Secondary sexual differentiation