- B.S., University of Dayton, 1972
- Ph.D., Harvard University, 1979
- Postdoc, Harvard Medical School, 1979-83
- National Institutes of Health
My laboratory investigates molecular and cellular mechanisms that regulate spermatogenesis, sperm motility and fertilization. A major focus of our current research is sperm energy metabolism, particularly the function of glycolytic isozymes with restricted expression in the male germline. Our gene targeting studies of two germ cell-specific isozymes provide compelling evidence that glycolysis is essential for sperm motility and male fertility in the mouse. Males lacking either glyceraldehyde 3-phosphate dehydrogenase-S (GAPDHS) or phosphoglycerate kinase 2 produce sperm with severe motility defects and very low ATP levels. GAPDHS has a unique N-terminus that is required for targeting this isozyme to the fibrous sheath, a cytoskeletal structure in the sperm flagellum that defines the limits of the principal piece (see figure). We also identified three new aldolase isoforms in mouse sperm, including two isoforms with novel N-terminal extensions that are tightly bound to the fibrous sheath. Distinctive features of the germ cell-specific glycolytic enzymes may be important for compartmentalization of glycolysis in the principal piece and/or altered activity of this key metabolic pathway.
We are using homology modeling, X-ray crystallography, and in silico docking studies to determine if the germ cell-specific glycolytic enzymes have distinct enzymatic properties. Two compounds identified in these analyses selectively inhibit GAPDHS. These studies underscore the utility of structure-based drug design and support the concept that sperm-specific glycolytic enzymes may be excellent contraceptive targets.
We are also studying the genetics of male infertility in collaboration with Dr. Fernando Pardo-Manuel de Villena in the Department of Genetics. The Collaborative Cross (CC), a large panel of recombinant inbred mouse lines, is being developed as a mammalian reference population for the analysis of complex traits. We are conducting extensive phenotypic and genotypic analyses of CC mouse lines that are becoming extinct. The high incidence of male infertility and the wide range of phenotypic defects observed, combined with the genetic structure of extinct and surviving CC lines, offer a unique opportunity to identify natural variation associated with male infertility.
- Goodson SG, Qiu Y, Sutton KA, Xie G, Jia W, O’Brien DA (2012) Metabolic substrates exhibit differential effects on functional parameters of mouse sperm capacitation. Biol Reprod 87:75, 1-15
- Collaborative Cross Consortium (2012) The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 190:389-401
- Sexton JZ, Danshina PV, Lamson DR, Hughes M, House AJ, Yeh LA, O’Brien DA, Williams KP (2011) Development and implementation of a high throughput screen for the human sperm-specific isoform of glyceraldehyde 3-phosphate dehydrogenase (GAPDHS). Curr Chem Genomics 5:30-41
- Goodson SG, Zhang Z, Tsuruta JK, Wang W, O’Brien DA (2011) Classification of mouse sperm motility patterns using an automated multiclass support vector machines model. Biol Reprod 84:1207-1215
- Lamson DR, House AJ, Danshina PV, Sexton JZ, Sanyang K, O’Brien DA, Yeh LA, Williams KP (2011) Recombinant human sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) is expressed at high yield as an active homotetrameric form in baculovirus-infected insect cells. Protein Expr Purif 75:104-113
- Goto M, O’Brien DA, Eddy EM (2010) Speriolin is a novel human and mouse sperm centrosome protein. Hum Reprod 25:1884-1894
- Vemuganti SA, Pardo-Manuel de Villena F, O’Brien DA (2010) Frequent and recent retrotransposition of orthologous genes in the glycolytic pathway. BMC Genomics 11:285
- Danshina PV, Geyer CB, Dai Q, Goulding EH, Willis WD, Kitto GB, McCarrey JR, Eddy EM, O’Brien DA (2010) Phosphoglycerate kinase 2 (PGK2) is essential for sperm function and male fertility. Biol Reprod 82:136-145
- Sawyer GM, Monzingo AF, Poteet EC, O’Brien DA, Robertus JD (2008) X-ray analysis of phosphoglycerate kinase 2, a sperm specific isoform from Mus musculus. Proteins 71:1134-1144
- Vemuganti SA, Bell TA, Scarlett CO, Parker CE, Pardo-Manuel de Villena F, O’Brien DA (2007) Three male germline-specific aldolase A isozymes are generated by alternative splicing and retrotransposition. Dev Biol 309: 18-31
- Buchold GM, Magyar PL, O’Brien DA (2007) Mice lacking cyclin-dependent kinase inhibitor p19Ink4d show strain-specific effects on male reproduction. Mol Reprod Dev 74: 1008-1020
- Buchold GM, Magyar PL, Arumugam R, Lee M, O’Brien DA (2007) Cyclin-dependent kinase inhibitors in the male reproductive axis. Mol Reprod Dev 74: 997-1007
- Yuan W, Leisner T, McFadden AW, Clark S, Hiller S, Maeda N, O’Brien DA, Parise L (2006) CIB1 is essential for mouse spermatogenesis. Mol Cell Biol 26: 8507-8514
- Krisfalusi M, Miki K, Magyar PL, O’Brien DA (2006) Multiple glycolytic enzymes are tightly bound to the fibrous sheath of mouse spermatozoa. Biol Reprod 75:270-278
- Miki K, Qu W, Goulding EH, Willis WD, Bunch DO, Strader LF, Perreault SD, Eddy EM, O’Brien DA (2004) Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility. Proc Natl Acad Sci USA 101:16501-16506
- Yang G, Zhang Y-L, Buchold GM, Jetten AM, O’Brien DA (2003) Analysis of germ cell nuclear factor transcripts and protein expression during spermatogenesis. Biol Reprod 68:1620-1630
- Akama TO, Nakagawa H, Sugihara K, Narisawa S, Ohyama C, Nishimura S-I, O’Brien DA, Moremen KW, Millán JL, Fukuda MN (2002) Germ cell survival through carbohydrate-mediated interaction with Sertoli cells. Science 295:124-127