Molecular basis of mammalian sexual determination: activation of Müllerian 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 differentiating gonadal ridge directs testicular morphogenesis, characterized by elaboration of Müllerian inhibiting substance (MIS) and testosterone. SRY and MIS each belong to conserved gene families that function in the control of growth and differentiation. Structural and biochemical studies of the DNA binding domain of SRY (the HMG box) revealed a protein-DNA interaction consisting of partial side chain intercalation into a widened minor groove. Functional studies of SRY in a cell line from embryonic gonadal ridge demonstrated activation of a gene-regulatory 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.
Haqq
C M
CM
Pediatric Surgical Research Laboratory, Massachusetts General Hospital, Boston 02114.
King
C Y
CY
Ukiyama
E
E
Falsafi
S
S
Haqq
T N
TN
Donahoe
P K
PK
Weiss
M A
MA
D000595:Amino Acid Sequence; D000818:Animals; D054304:Anti-Mullerian Hormone; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005837:Genitalia, Male / Q000196:embryology*; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009095:Mullerian Ducts; D009687:Nuclear Proteins; D012733:Sex Differentiation / Q000235:genetics*; D051876:Sex-Determining Region Y Protein; D013735:Testicular Hormones / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D006023:Glycoproteins; D006131:Growth Inhibitors; D009687:Nuclear Proteins; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D013735:Testicular Hormones; D014157:Transcription Factors; D054304:Anti-Mullerian Hormone; D004247:DNA