Gordon D. Niswender, PhD
University Distinguished Professor
Office: W127 ARBL Building, Foothills Campus
I participate in the graduate course in Reproductive Physiology (BMS 640) and mentor graduate students and postdoctoral fellows.
Research Interests -- Reproductive Endocrinology
In domestic animals and humans, 25-50% of pregnancies are lost during the first month. Most of this early embryonic wastage is due to insufficient secretion of progesterone.
Progesterone is required for normal pregnancy in all mammalian species. Therefore, studies in our laboratory are focused upon the molecular mechanisms which control the synthesis and secretion of progesterone. We first determined that there are two types of steroidogenic cells in the corpus luteum and that the second messenger pathways which control the secretion of progesterone are different in the two cell types.
Luteinizing hormone (LH) stimulates the secretion of progesterone from small luteal cells approximately 10- to 20-fold. However, small luteal cells only produce 15 to 20% of the progesterone secreted from the corpus luteum. Large luteal cells produce >80% of the progesterone due to the presence of a constituitively active form of protein kinase (PK)A which increases the activity of a number of steroidogenic proteins by phosphorylation. One of the major phosphorlyated proteins is steroidogenic acute regulatory protein (StAR) which transports cholesterol to the mitochondrial membrane, the rate-limiting step in progesterone biosynthesis.
Binding of PGF2a to its receptor on large luteal cells: 1) stimulates the secretion of oxytocin which acts on small luteal cells and the uterus; 2) activates PKC which inhibits steroidogenesis in large luteal cells; 3) activates COX-2 and stimulates secretion of PGF2a from large luteal cells; and 4) activates PGF2a-gated calcium channels which increase intracellular levels of calcium leading to apoptotic death of the large luteal cells. Binding of oxytocin to small luteal cells results in increased intracellular levels of calcium and death of this cell type by apoptotic mechanisms.
Click here for an animated PowerPoint presentation of the cellular mechanisms involved in the control of progesterone secretion and luteolysis.
Future research is focused on the role of progesterone and luteal membrane receptors for this hormone in regulating the actions of oxytocin and PGF2a on luteal cells. Experiments are also planned to determine the luteal cellular events which are altered by the presence of an embryo in the uterus. The corpus luteum must continue to secrete progesterone for pregnancy to be maintained in all mammalian species.
Juengel JL, Haworth JD, Rollyson MK, Silva PJ, McIntush EW, Sawyer HR, Niswender GD. 2000. Effect of dose of prostaglandin F2a on steroidogenic components and oligonucleosomes in ovine luteal tissue. Biol Reprod 62:1047-1051.
Silva PJ, Juengel JL, Rollyson MK, Niswender GD. 2000. Prostaglandin metabolism in the ovine corpus luteum: catabolism of prostaglandin F2a (PGF2a) coincides with resistance of the corpus luteum to PGF2a. Biol Reprod 63:1229-1236.
West LA, Horvat RD, Roess DA, Barisas BG, Juengel JL, Niswender GD. 2001. Steroidogenic acute regulatory protein and peripheral-type benzodiazepine receptor associate at the mitochondrial membrane. Endocrinology 142:502-505.
Niswender GD. 2002. Molecular control of luteal secretion of progesterone. Reproduction 123:333-339.
Ashley RL, Clay CM, Farmerie TA, Niswender GD, Nett TM. 2006. Cloning and characterization of an intracellular seven transmembrane progesterone receptor that mediates calcium mobilization. Endocrinology 147:4151-4159.
Niswender GD, Davis TL, Griffith RJ, Bogan RL, Monser K, Bott RC, Bruemmer JE, Nett TM. 2006. Judge, jury and executioner: The auto-regulation of luteal function. In: Reproduction in Domestic Ruminants VI. JL Juengel, JF Murray, MF Smith (eds), Nottingham University Press, Nottingham, UK, pp 191-206.
Bogan RL, Davis TL, Niswender GD. 2007. Peripheral-type benzodiazepine receptor (PBR) aggregation and absence of steroidogenic acute regulatory protein (StAR)/PBR association in the mitochondrial membrane as determined by bioluminescence resonance energy transfer (BRET). J Steroid Biochem Molec Biol 104:61-67.
Bogan RL, Niswender GD. 2007. Constitutive steroidogenesis in ovine large luteal cells is mediated by tonically active protein kinase A. Biol Reprod. In Press.