|William L. Miller
||William Neal Reynolds Professor
B.S., Biochemistry, Bucknell University, Lewisburg PA, 1965
Ph.D., Cornell University, Ithaca NY, 1970
Office: 28 Polk Hall
Phone: (919) 515-5762 (office)
Phone: (919) 515-5763 (lab)
Fax: (919) 515-2047
- Transcription Factors Regulating Reproduction
Click on Picture Below for Lab Members
Introduction: Our laboratory works on gene transcription, focusing on follicle-stimulating hormone (FSH) which is controlled by six or more hormones in vivo. FSH is produced in pituitary gonadotropes in all mammals and is essential for folliculogenesis (egg production). It is important for spermatogenesis as well. Its synthesis and secretion depend on production of its beta subunit (FSHb) which we have studied in depth. Our main focus is on transcriptional regulation of FSHb by transforming growth factor beta (TGFb) family members, mainly activins and bone morphogenetic proteins (BMPs). Shown below is the origin of FSH (pituitary gonadotropes) and the functions of FSH: egg and sperm production.
Focus: Transcriptional regulation of FSHb has been studied in primary gonadotropes (cultured from fresh pituitaries) and transformed gonadotrope cell lines. Molecular biology has been used to prepare plasmids in which expression of luciferase (a reporter gene) is driven by the FSHb promoter in transformed gonadotropes in culture and also in transgenic animals to understand FSHb regulation at a molecular level. Of the six (or more?) hormones that control FSHb transcription, we have chosen to study TGFb family members because they seem to have the greatest influence. Furthermore, as their name implies, TGFb family members are often associated with transformation that occurs during tumor formation. Therefore, understanding how these molecules affect transcription has the dual purpose of understanding FSH regulation as well as characterizing molecules involved in cancer. As noted below, TGFb family members (in this case activin) bind cell surface membranes and transmit their signal to the genome through Smad transcription factors.
Activin is the most powerful natural inducer of FSHb transcription. We aim to determine how this hormone induces FSHb at the gene AND receptor levels. Using molecular biology techniques the FSHb promoter is being dissected to locate activin response elements. Also, receptor and second messenger molecules are being analyzed for their role in FSHb induction. Ultimately, we hope to identify the Smad or other molecules? that bind the FSHb promoter to induce expression. Although it is known that an activin-like molecule induces FSHb transcription, it is not known exactly which one(s). We plan to identify the exact TGFb family member(s) involved. This project uses sophisticated techniques in biochemistry and attacks a basic transcriptional problem that will result in knowledge with practical importance for reproductive biology and TGFb studies on many tissues.
1. Huang HJ, Sebastian J, Strahl BD, Wu JC, Miller WL (2001) The Promoter for the Ovine Follicle-Stimulating Hormone-β Gene (FSHβ) confers FSHβ-Like
Expression on Luciferase in Transgenic Mice: Regulatory Studies In Vivo and In Vitro. Endocrinology 142:2260-2266
2. Huang HJ, Sebastian J, Strahl BD, Wu JC, Miller WL (2001) Transcriptional Regulation of the Ovine Follicle-stimulating Hormone-β Gene by Activin and
gonadotropin-Releasing Hormone (GnRH): Involvement of Two Proximal activator Protein-1 Sites for GnRH Stimulation. Endocrinology 142:2267-74
3. Huang HJ, Wu JC, Su P, Zhirnov O, and Miller WL (2001) A Novel Role for Bone Morphogentic Proteins in the synthesis of Follicle-Stimulating Hormone.
4. Pernasetti F, Vasilyev VV, Rosenberg SB, Bailey JS, Huang HJ, Miller WL, Mellon PL (2001) Cell-Specific transcriptional Regulation of Follicle-Stimulating
Hormone-β by Activin and Gonadotropin-Releasing Homrone in the LβT2 Pituitary Gonadotrope Cell Model. Endocrinology 142:2284-2295.
5. Miller WL, Shafiekermani F, Strahl BD, Huang HJ, (2002) The nature of GnRH induction of FSH. TEMS, 13: 257-262.