MOLECULAR-BASIS OF MAMMALIAN SEXUAL DETERMINATION - ACTIVATION OF MULLERIAN-INHIBITING SUBSTANCE GENE-EXPRESSION BY SRY

The pathway of male sexual development in mammals is initiated by SRY, a gene on the short arm of the Y chromosome. Its expression in the di fferentiating gonadal ridge directs testicular morphogenesis, characte rized by elaboration of Mullerian inhibiting substance (MIS) and testo sterone. SRY and MIS each belong to conserved gene families that funct ion in the control of growth and differentiation. Structural and bioch emical studies of the DNA binding domain of SRY (the HMG box) revealed a protein-DNA interaction consisting of partial side chain intercalat ion into a widened minor groove. Functional studies of SRY in a cell l ine from embryonic gonadal ridge demonstrated activation of a gene-reg ulatory pathway leading to expression of MIS. SRY molecules containing mutations associated with human sex reversal have altered structural interactions with DNA and failed to induce transcription of MIS.