Errol R. Norwitz, M.D., Ph.D.

Associate Professor, Yale University School of Medicine
Associate Director, Division of Maternal-Fetal Medicine
Fellowship Director, Division of Maternal-Fetal Medicine
Dept of Obstetrics, Gynecology & Reproductive Sciences
Yale-New Haven Hospital
333 Cedar Street, FMB 308
New Haven, CT 06520-8063
Tel: (203) 785-4825
Fax: (203) 737-1883
errol.norwitz@yale.edu

Research

Major research interest: Molecular mechanisms of GnRH receptor gene regulation

Other research interests: Cytokine gene polymorphisms and adverse pregnancy outcome; Molecular mechanism(s) of human parturition, both term and preterm; Application of proteomic technology to normal and abnormal pregnancy outcomes; Clinical management of post-term pregnancy

“Molecular mechanisms of GnRH receptor gene regulation”

The hypothalamic decapeptide, GnRH, is critical to mammalian reproductive development and function. At the level of the anterior pituitary, GnRH binds to its receptor, the GnRH receptor (GnRHR), on the surface of pituitary gonadotropes to affect the synthesis and intermittent release of the gonadotropins, LH and FSH. These hormones then enter the systemic circulation to regulate gonadal function, including steroid hormone synthesis and gametogenesis. The response of pituitary gonadotropes to GnRH correlates directly with the concentration of GnRHR on the cell surface, which is mediated in large part at the level of gene expression.

The overall objective of this project is to understand in detail the molecular mechanisms involved in the hormonal regulation and tissue-specific expression of the GnRHR gene in the mouse. Over the past few years, we have contributed significantly to our understanding of how this gene is regulated. We have localized GnRH-responsiveness to two DNA sequences at -292/-285 (a novel sequence designated Sequence Underlying Responsiveness to GnRH-1 [SURG-1]) and the AP-1 consensus binding sequence at -276/-269, and demonstrated that this response is mediated via protein kinase C (Norwitz et al., J Biol Chem 1999; 274:867). We have shown that activin is able to upregulate GnRHR gene expression and to augment the response of this gene to GnRH stimulation (Norwitz et al., Endocrinology 2002; 143:985). Most recently, we defined a novel cis-regulatory element within -387/-308 of the mGnRHR gene promoter that is responsible for this synergistic interaction. This element is comprised of an overlapping SBE and newly characterized non-consensus AP-1 binding sequence that mediates transactivation of the mGnRHR gene by both GnRH and activin (Norwitz et al., J Biol Chem 2002; 277:37469).

Recent studies have identified a second cell surface receptor for GnRH in mammals (designated GnRHR-II), which binds and is activated by a structurally-related ligand, GnRH-II. Preliminary data suggests that GnRH may regulate placental hCG production and that placental tissues bind GnRH-II with a much greater affinity than GnRH-I (GnRH). We hypothesize that GnRH-I and/or GnRH-II produced by fetal cytotrophoblast cells act through their cognate receptors on the surface of syncytiotrophoblast to regulate hCG production and thereby maintain early pregnancy. We are currently working to prove this hypothesis. We expect that the results of this research will help guide the development of new and innovative approaches to the treatment of clinical disorders in which dysfunction of hCG production has been implicated, including subfertility, recurrent pregnancy loss, and various malignancies of the reproductive tract (such as choriocarcinoma and ovarian endodermal sinus tumor).

Recent Publications

Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med 2001; 345:1400-8.

Norwitz ER, Xu S, Jeong K-H, Bédécarrats GY, Winebrenner LD, Chin WW, Kaiser UB. Activin A augments GnRH-mediated transcriptional activation of the mouse GnRH receptor gene. Endocrinology 2002; 143:985-97.

Norwitz ER, Xu S, Xu J, Spiryda LB, Park JS, Jeong K-H, McGee EA, Kaiser UB. Direct binding of AP-1 (Fos/Jun) proteins to a SMAD binding element facilitates both GnRH- and activin-mediated transcriptional activation of the mouse GnRH receptor gene. J Biol Chem 2002; 277:37469-78.

Bédécarrats GY, O’Neill FH, Norwitz ER, Kaiser UB, Teixeira J. Regulation of gonadotropin gene expression by müllerian inhibiting substance. Proc Nat Acad Sci U S A 2003; 100:9348-9353.

McElrath TF, Colon I, Hecht J, Tanasjavic MJ, Norwitz ER. Neonatal respiratory distress syndrome as a function of gestational age and an assay for surface-to-albumin ratio. Obstet Gynecol 2004; 103:463-8.