This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bair, S. R.
Right arrow Articles by Mellon, S. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bair, S. R.
Right arrow Articles by Mellon, S. H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2004, p. 5383-5390, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5383-5390.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

Susanna R. Bair and Synthia H. Mellon*

Department of Obstetrics, Gynecology, and Reproductive Sciences, The Center for Reproductive Sciences, and The Metabolic Research Unit, University of California, San Francisco, San Francisco, California 94143

Received 6 October 2003/ Returned for modification 20 November 2003/ Accepted 19 March 2004

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 C17,20-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.

* Corresponding author. Mailing address: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 513 Parnassus Ave., Box 0556, San Francisco, CA 94143-0556. Phone: (415) 476-5329. Fax: (415) 753-3271. E-mail: mellon{at}cgl.ucsf.edu.

Molecular and Cellular Biology, June 2004, p. 5383-5390, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5383-5390.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Shi, Y., Schonemann, M. D., Mellon, S. H. (2009). Regulation of P450c17 Expression in the Early Embryo Depends on GATA Factors. Endocrinology 150: 946-956 [Abstract] [Full Text]  
  • Rocha, J. S., Bonkowski, M. S., Franca, L. R., Bartke, A. (2007). Mild Calorie Restriction Does Not Affect Testosterone Levels and Testicular Gene Expression in Mutant Mice. Exp. Biol. Med. 232: 1050-1063 [Abstract] [Full Text]  
  • Sher, N., Yivgi-Ohana, N., Orly, J. (2007). Transcriptional Regulation of the Cholesterol Side Chain Cleavage Cytochrome P450 Gene (CYP11A1) Revisited: Binding of GATA, Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein and Activating Protein (AP)-1 Proteins to a Distal Novel Cluster of cis-Regulatory Elements Potentiates AP-2 and Steroidogenic Factor-1-Dependent Gene Expression in the Rodent Placenta and Ovary. Mol. Endocrinol. 21: 948-962 [Abstract] [Full Text]  
  • Mellon, S. H., Bair, S. R., Depoix, C., Vigne, J.-L., Hecht, N. B., Brake, P. B. (2007). Translin Coactivates Steroidogenic Factor-1-Stimulated Transcription. Mol. Endocrinol. 21: 89-105 [Abstract] [Full Text]  
  • Cole, B., Hensinger, K., Maciel, G. A. R., Chang, R. J., Erickson, G. F. (2006). Human Fetal Ovary Development Involves the Spatiotemporal Expression of P450c17 Protein. J. Clin. Endocrinol. Metab. 91: 3654-3661 [Abstract] [Full Text]  
  • Liu, Y., Yao, Z.-X., Bendavid, C., Borgmeyer, C., Han, Z., Cavalli, L. R., Chan, W.-Y., Folmer, J., Zirkin, B. R., Haddad, B. R., Gallicano, G. I., Papadopoulos, V. (2005). Haploinsufficiency of Cytochrome P450 17{alpha}-Hydroxylase/17,20 Lyase (CYP17) Causes Infertility in Male Mice. Mol. Endocrinol. 19: 2380-2389 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»