title: Deletion of the mouse P450c17 gene causes early embryonic lethality.
abstract: Dehydroepiandrosterone (DHEA), a 19-carbon precursor of sex steroids, is abundantly produced in the human but not the mouse adrenal. However, mice produce DHEA and DHEA-sulfate (DHEAS) in the fetal brain. DHEA stimulates axonal growth from specific populations of mouse neocortical neurons in vitro, while DHEAS stimulates dendritic growth from those cells. The synthesis of DHEA and sex steroids, but not mouse glucocorticoids and mineralocorticoids, requires P450c17, which catalyzes both 17 alpha-hydroxylase and 17,20-lyase activities. We hypothesized that P450c17-knockout mice would have disordered sex steroid synthesis and disordered brain DHEA production and thus provide phenotypic clues about the functions of DHEA in mouse brain development. We deleted the mouse P450c17 gene in 127/SvJ mice and obtained several lines of mice from two lines of targeted embryonic stem cells. Heterozygotes were phenotypically and reproductively normal, but in all mouse lines, P450c17(-/-) zygotes died by embryonic day 7, prior to gastrulation. The cause of this early lethality is unknown, as there is no known function of fetal steroids at embryonic day 7. Immunocytochemistry identified P450c17 in embryonic endoderm in E7 wild-type and heterozygous embryos, but its function in these cells is unknown. Enzyme assays of wild-type embryos showed a rapid rise in 17-hydroxylase activity between E6 and E7 and the presence of C(17,20)-lyase activity at E7. Treatment of pregnant females with subcutaneous pellets releasing DHEA or 17-OH pregnenolone at a constant rate failed to rescue P450c17(-/-) fetuses. Treatment of normal pregnant females with pellets releasing pregnenolone or progesterone did not cause fetal demise. These data suggest that steroid products of P450c17 have heretofore-unknown essential functions in early embryonic mouse development.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, The Center for Reproductive Sciences, and The Metabolic Research Unit, University of California, San Francisco, 94143, USA.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Bair
authors.forename: Synthia H
authors.initials: SH
authors.lastname: Mellon
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000096:biosynthesis; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D005260:Female; D005313:Fetal Death / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011247:Pregnancy; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000502:physiology*
chemical_list: D006907:17-alpha-Hydroxypregnenolone; D003687:Dehydroepiandrosterone; D013254:Steroid 17-alpha-Hydroxylase