WUSTL
   

Gynecology/Oncology
 : 
Joint Members Research Interests and Labs

 

Irving Boime , Ph.D.
Professor
Developmental Biology
Obstetrics and Gynecology
Biochemistry Program
Molecular Cell Biology Program
Developmental Biology Program

Office Phone: 314-362-2556
Lab Phone: 314-362-2519
Other Phone: 314-362-2673
FAX: 314-361-3560
Box: 8103
Lab Address: 375 McDonnell Medical Sciences Building
Email: iboime@wustl.edu
Keywords: biochemistry; carbohydrate; protein structure; signal transduction; intracellular trafficking
Short Research Description: Placental and pituitary hormone genes.
Research Abstract:
Human chorionic gonadotropin (CG), lutropin (LH), follitropin (FSH), and thyrotropin (TSH) are a family of heterodimeric glycoprotein hormones that share a common a subunit but differ in their hormone-specific ß? subunits. One or more of these hormones is essential for gonadal development, and for maintaining pregnancy and thyroid function. Using site-directed mutagenesis, our laboratory investigates structural determinants that govern the unique post-translational modifications of the related placental and pituitary glycoprotein hormones. These hormones undergo specific modifications and have unique biologic activities. Together with DNA mediated transfection techniques, monoclonal antibody screening, and protein and carbohydrate characterization, the laboratory is examining the regions critical for chaperone interactions in the folding and the differential sorting of these heterodimeric hormones. Studies are also underway for determining the ligand determinants that are responsible for the transducing signals in the hormone-receptor complex. A critical feature of these hormones is their unique secretion patterns. LH is secreted through a regulated secretory pathway, i.e. it is released by secretagogue, whereas FSH is primarily secreted constitutively. The oligosaccharides on these glycoproteins are hormone specific. We are currently testing models addressing the hypothesis that the carbohydrates play a critical role in FSH/LH sorting. FSH-LH ß chimeras and point mutants are currently designed to identify sequences that govern their unique secretion patterns. Informative LH and FSH variants in cell-culture assays will be expressed in pituitaries from transgenic mice. The ability to reroute FSH and LH in vivo would represent an important model for gonadal dysfunction and potentially provide a novel way to examine normal and ultimately pathophysiological events in the human reproductive tract.
Selected Publications:
Jablonka-Shariff A, Boime I. Luteinizing hormone and follicle-stimulating hormone exhibit different secretion patterns from cultured Madin-Darby canine kidney cells. Biol Reprod 2004 70:649-655.

Garcia-Campayo V, Sugahara T, Boime I. Unmasking a new recognition signal for O-linked glycosylation in the carboxyl terminal sequence of the human chorionic gonadotropin ß subunit. Mol Cell Endocrinol 2002 194:63-70.

Jablonka-Shariff A, Garcia-Campayo V, Boime I. Evolution of lutropin to chorionic gonadotropin generates a specific routing signal for apical release in vivo. J Biol Chem 2002 277:879-882.

Tim B. Schedl , Ph.D.
Professor
Genetics
Molecular Genetics and Genomics Program
Developmental Biology Program
BiomedRAP Program

Office Phone: 314-362-6162
Lab Phone: 314-362-6164
Other Phone:
FAX: 314-362-7855
Box: 8232
Lab Address: 870 McDonnell Medical Sciences Building
Email: ts@genetics.wustl.edu
Website: http://www.genetics.wustl.edu/tslab/
Keywords: germ cells; C. elegans; genetics; development; functional genomics
Short Research Description: Control of germline stem cells and meiotic development in C. elegans.
Research Abstract:
Germ cells are unique in animals as they are the means by which genetic material and cytoplasmic constituents are passed through generations. We are studying three processes that are critical for germ cell development: 1) the decision of stem cells to proliferate versus initiate meiotic development; 2) control of progression through meiotic prophase and its coordination with oogenesis; and 3) control of germline sex determination. Little is know about these processes in any animal. We are utilizing Caenorhabditis elegans for our studies because of its transparency, tractable genetics and functional genomics.

The three germline processes are each initially regulated by cell-cell signaling. GLP-1/Notch receptor signaling controls the decision to proliferate versus initiate meiosis, RAS-ERK MAP kinase signaling acts at multiple points to control meiotic prophase cell cycle transitions and oogenesis, while the somatic gonad sex determination signal is unknown. GLD-1 is a translational regulator that functions in all three processes. We use genetic analysis, including high-throughput RNAi screens in sensitized genetic backgrounds, to identify genes that are necessary for different steps in germline development and to define the regulatory pathways in which they function. We have identified a number of new genes that function downstream of GLP-1/Notch signaling in redundant pathways to repress germline stem cell proliferation and promote initiation of meiotic development; disruption of particular sets of these pathways causes germline tumor formation. We have used a combined computational, RNAi and biochemical approach to identify novel, evolutionarily conserved, phosphorylation targets of ERK MAP kinase that execute steps in oogenesis.
Selected Publications:
Nayak S, Goree J, Schedl T. fog-2 and the evolution of hermaphrodite germline sex determination in the C. elegans. PLoS Biology 2005 3:57-71.

Schumacher B, Hanazawa M, Lee MH, Nayak S, Volkmann K, Hoffman R, Hengartner M, Schedl T, Gartner A. Translational repression of C. elegans p53 by GLD-1 regulates DNA damage induced apoptosis. Cell 2005 120:357-368.

Hansen D, Hubbard J, Schedl T. Multi-pathway control of the proliferation versus meiotic development decision in the C. elegans germ line. Dev Biol 2004 268:342-357.

Hansen D, Wilson-Berry L, Dang T, Schedl T. Control of the proliferation versus meiotic development decision in the C. elegans germline through regulation of GLD-1 protein accumulation. Development 2004 131:93-104.

Lee MH, Schedl T. Translational repression by GLD-1 protects its mRNA targets from non-sense mediated mRNA decay in C. elegans. Genes Dev 2004 18:1047-1059.