PARENT SESSION
MINISYMPOSIUM XIV. Genetics of Sex Determination and Early Gonadal Development.
11:00 AM-12:30 PM
Harborside A & B
Chair: Ingraham, Holly¹, ¹

(M42) DOSAGE-SENSITIVE SEX REVERSAL IN MAMMALS.

Vilain, Eric¹, ¹ UCLA Departments of Human Genetics and Pediatrics, Los Angeles, CA

ABSTRACT- Sex determination orients development toward sexually dimorphic individuals, male or female. In mammals, male sex determination is triggered by a primary signal, encoded by the testis-determining factor SRY, localized on the Y chromosome. Subsequently, a complex network of genes, most of them still unknown, is regulated and leads to male sexual differentiation, including development of external and internal genitalia and sexual behavior. Disorders of the sex determination pathway result in malformations of the genitalia, varying from sexual ambiguity to complete sex reversal (XY female, XX male). Management of intersexuality critically depends on a precise diagnosis, which depends in turn on specific knowledge of their molecular pathophysiology. Defective molecular mechanisms of sex determination are responsible for the abnormal development of the gonads, and for sexual ambiguity. Until recently, only transcription factors such as SRY, SOX9, DAX1, WT1, and SF1 were known to be involved in this process, as they were responsible, when mutated, for abnormal gonadal development and sexual ambiguity. We and others showed that Wnt-4 was a new sex-determining signaling molecule responsible for masculinization of XX mouse pups when deleted, and for XY sex reversal when duplicated and overexpressed in humans. A transgenic mouse model for Wnt-4 overexpression has been designed and its phenotype will be discussed. We have shown that Wnt-4 upregulates Dax1 in a mouse Leydig tumor cell line (MLTC-1) and in a mouse Sertoli cell line (TM-4). This biochemical evidence is consistent with clinical data in suggesting a stimulatory effect of Wnt-4 on DAX-1 expression: a duplication of Wnt-4 results in XY sex reversal as does a duplication of DAX-1. Altogether, these observations suggest that mammalian sex determination is sensitive to dosage at multiple steps in its pathway. Further dissection of the molecular pathway of mammalian sex determination will be crucial in understanding the development of the gonads, and the pathophysiology of human disorders of sex determination.

KEY WORDS: Gonad, Sex determination, Wnt-4, Dax1