Nilson, John H.
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MBioS 504

Research Interests
Gonadotropins from pituitary gonadotropes regulate gametogenesis and steroidogenesis and therefore play essential roles in establishing normal gonadal function. A quartet of genes completes the signature of a functional gonadotrope: Cga, Lhb, Fshb, and Gnrhr. Cga encodes the a subunit common to all heterodimeric glycoprotein hormones. Lhb and Fshb encode ß-subunits that provide LH and FSH with their unique biological activity. Finally, Gnrhr encodes a G-protein coupled receptor that binds GnRH and transduces its signal.

GnRH regulates gonadotrope function through a complex transcriptional network comprising over 75 genes. Transcriptional responsiveness to GnRH starts with the integration of signals from a cascade of protein kinases that regulate transcription of three members of the immediate early gene family (IEG): Egr1, Jun, and Atf3. These IEGs encode DNA-binding proteins that ultimately confer GnRH responsiveness to Cga, Lhb, Fshb, and Gnrhr. Regulated expression of these signature genes also requires another DNA-binding protein, the orphan receptor SF1, that acts permissively to render the genes responsive to GnRH. In the case of the Lhb promoter, activity of SF1 also requires the binding of ß-catenin, a co-activator and member of the canonical WNT signaling pathway.

Currently, our laboratory is testing three major hypotheses that will deepen our understanding of how the GnRH signal crosses the transcriptional network and culminates in the regulation of the four signature genes. First, while it is clear that GnRH regulates transcription of Egr1 through convergence of multiple signaling pathways, we postulate that post-transcriptional and post-translational mechanisms contribute to the concentration and activity of the EGR1 protein as they do for other members of the IEG family. Second, new evidence indicates that GnRH regulates ß-catenin via cross-talk with downstream members of the canonical WNT signaling pathway, suggesting a new signaling route for regulating expression of Jun and possibly other IEG mRNAs. Third, we propose that ß-catenin also acts independently of GnRH to support the permissive role of SF1 in allowing all four signature genes to respond to GnRH.

We are testing these hypotheses in gonadotrope cell lines and in transgenic mice using a variety of molecular tools including transfection, transgenesis, and RNAi. Our long term goal is understand the functional pathways that connect GnRH to all of the genes that respond to the hormone.

Publications (Selected References)
Salisbury TB, Binder AK, Grammer JC, Nilson JH 2007 Maximal activity of the luteinizing hormone beta-subunit gene requires beta-catenin. Mol Endocrinol 21:963-971

Parakh TN, Hernandez JA, Grammer JC, Weck J, Hunzicker-Dunn M, Zeleznik AJ, Nilson JH 2006 Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin. Proc Natl Acad Sci U S A 103:12435-12440

Jorgensen JS, Quirk CC, Nilson JH 2004 Multiple and overlapping combinatorial codes orchestrate hormonal responsiveness and dictate cell-specific expression of the genes encoding luteinizing hormone. Endocr Rev 25:521-542

Mohammad HP, Seachrist DD, Quirk CC, Nilson JH 2004 Reexpression of p8 contributes to tumorigenic properties of pituitary cells and appears in a subset of prolactinomas in transgenic mice that hypersecrete luteinizing hormone. Mol Endocrinol 18:2583-2593

Mohammad HP, Abbud RA, Parlow AF, Lewin JS, Nilson JH 2003 Targeted overexpression of luteinizing hormone causes ovary-dependent functional adenomas

Quirk CC, Seachrist DD, Nilson JH  2003 Embryonic expression of the luteinizing hormone beta gene appears to be coupled to the transient appearance of p8, a high mobility group-related transcription factor. J Biol Chem 278:1680-1685

Jorgensen JS, Nilson JH 2001 AR suppresses transcription of the LHbeta subunit by interacting with steroidogenic factor-1. Mol Endocrinol 15:1505-1516

Jorgensen JS, Nilson JH 2001 AR suppresses transcription of the alpha glycoprotein hormone subunit gene through protein-protein interactions with cJun and activation transcription factor 2. Mol Endocrinol 15:1496-1504

Quirk CC, Lozada KL, Keri RA, Nilson JH 2001 A single Pitx1 binding site is essential for activity of the LHbeta promoter in transgenic mice. Mol Endocrinol 15:734-746

Lab Members

Jean Grammer, Senior Research Associate
April Binder, Graduate Student
Ted Chauvin, Postdoctoral Scientist
Jennifer Hernandez, Postdoctoral Scientist
Maria Herndon, Postdoctoral Scientist
Travis Salisbury, Postdoctoral Scientist