Chapter 1. Introduction

The sex determination process, in which the undifferentiated, “bipotential” embryonic gonads become either testes or ovaries is guided by genes and testicular hormones. So far the development and differentiation of the gonad is better known in males than in females. Sry was the first gene identified as playing a role in sex determination (Koopman et al. 1991), and since then several others, such as Wilms tumor suppressor gene 1 (Wt1), steroidogenic factor 1 (Sf1), Sox9 and Dax-1, have been shown to be involved in this process (Swain & Lovell-Badge 1999). Traditionally, the female pathway of sexual differentiation has been considered a default alternative; occurring only due to absence of the Y-chromosome and testicular hormones, so that it lacks any active signalling.

Wnts are intercellular growth and differentiation factors, which are involved in a variety of developmental processes (Miller 2002). One member of this large gene family of secreted and soluble glycoproteins, Wnt-4, has been shown to be needed for the development of the kidney (Stark et al. 1994), pituitary gland (Treier et al. 1998), mammary gland (Brisken et al. 2000) and thymus (Mulroy et al. 2002) in the mouse. Wnt-4-deficient mice are not viable and die soon after birth, most likely due to dysfunction of the kidneys.

The present study was focused on the role of Wnt-4 in the sex determination process and the development of the adrenal gland. Wnt-4 was shown to be active in female development, so that its absence led to partial female-to-male sex reversal. In addition Wnt-4-deficient mice were shown to have problems in the development of the adrenal gland cortex.