Newsletter * Center for Reproductive Science (CRS)

A publication of the Center for Reproductive Science
Northwestern University, Evanston and Chicago
Fall 2000 Volume 1 No. 3

The faculty members of the Center, and their students, achieved numerous recognitions recently, which are detailed on page 2 of this newsletter. Congratulations to all of you.

We are also proud of our website at http://www.northwestern.edu/center-for-reproductive-science. It was constructed by the Center secretary Mr. Mukhtar Rafiqi. Check it out – it contains information about research, grants, and awards for trainees and back issues of this newsletter. If you are a faculty member of the Center make sure your description is accurate. If you have not yet given him a picture to be included please do so. The site is used by prospective graduate students and post-docs, as well as by undergraduates at Northwestern.

Research and teaching in the reproductive sciences is highly collaborative – one of the features of our field that I personally have found most exciting. Several of the CRS faculty are teaching a course at Woods Hole each summer. The course is Frontiers in Reproduction: Molecular and Cellular Concepts (FIR). It is an intensive six-week laboratory and lecture course for 16 young independent scientists and physicians and advanced postdoctoral fellows seeking comprehensive and sophisticated training in research strategies and state-of-the-art methods on cellular, immunological and molecular biological approaches in reproductive biology. The course is taught at the Marine Biological Laboratories in Woods Hole, Massachusetts and will next be held May 24-July 1, 2001. The course is co-directed by Drs. Gerald Schatten (Oregon Health Sciences University), Joan Hunt (University of Kansas) and Kelly Mayo (Northwestern University). In addition to Mayo, CRS members Teresa Woodruff and Andy Shenker are on the course faculty, and CRS member Larry Jameson participated in the initial FIR course organizing committee.

Valerie Sepiashvili joined the Center as Program Assistant-2 on July 24th replacing Ila Allen. Valerie has a Bachelor of Arts degree from University of Illinois at Chicago. Valerie handles the ordering, paying of invoices, and she makes sure all work-study students get a paycheck.

Remember – with a growing concern about an increasing world population and a deteriorating environment —Reproduction matters
—Neena Schwartz

Keynote Speaker: Dr. Jeffrey Rosen, Bell Professor of Cell Biology, Baylor College of Medicine, Houston, TX. "Mammary Gland Development and Breast Cancer Insights from Transgenic and Knockout Mouse Models", Time: 3:50-4:50 PM.

Visit Dr. Rosen's web site www.bcm.tmc.edu/mcb/faculty/rosen.html
Thirty-five abstracts have been received from trainees. Fourteen will be presented orally, and the others in a poster session. Contact Mukhtar Rafiqi (mrafiqi@northwestern.edu, 847/491-5767) for further information.

Several faculty in the Center have recently received awards or been recognized for their excellence in research and leadership.

Joe Takahashi of the Department of Neurobiology and Physiology, has been elected to the American Academy of Arts and Sciences. Joe was the coauthor, with Fred Turek, of the CRS-Research Notes column in the Winter 2000 issue of Reproduction Matters, which discussed their work on the circadian clock. Joe’s research group discovered the mouse gene CLOCK.

Catherine Woolley, Department of Neurobiology and Physiology, won the Cajal Club Cortical Explorer Award in 2000 for her work on the effects of estrogens on neural cell structure and function.

Jim Bartles, Department of Cell and Molecular Biology, has been appointed to the American Cancer Society Cell Structure and Metastasis Peer Review Committee.

Larry Jameson has been appointed Chairman of the Department of Medicine at the Medical School, replacing Dr. Lew Landsberg, who has become Dean

Teresa Woodruff, Department of Neurobiology and Physiology, and Department of Medicine received the Richard E. Weitzman Award for her work on basic and clinical aspects of the hormone inhibin from the Endocrine Society at the Toronto meeting in June 2000. This award is presented annually to an "exceptionally promising young investigator" who is under 40 years of age. (See photograph below and Endocrinology 141:3046, 2000 for the citation). After the meeting, Teresa and Bill Lowe (Medicine) attended the Toronto Blue Jays vs. Boston Red Sox game and Bill caught a Carl Everett fly ball.

mayoWoodruffSchwartz.jpg (65293 bytes)
Kelly Mayo, Teresa Woodruff and Neena Schwartz in Toronto
after presentation of the award to Woodruff.
(Photography by Chuck Giorno Photography, Alexandria, VA 22304)

Postdoctoral Fellow Dr. Dan Bernard has been awarded the prestigious Lalor Foundation Award for work in Reproductive Sciences.

Tim Provias who has just graduated from the College of Arts and Science, majoring in Biology and Economics, was awarded a "Go to Meeting" award from the Center in order to go to the Toronto to present a poster at the 2000 Endocrine Society meeting. His research with Andy Shenker in Pediatrics on "Incomplete clinical penetrance of an activating mutation in helix 2 of the luteinizing hormone receptor" also received support from the Undergraduate research grant program. He graduated cum laude and also received the David Shemin prize. Two other college of Arts & Science students, Adam Butensky-Bartlett and David Sears, working with Shenker, also received award from Northwestern for their summer research.

Elliot Lee, in his senior year as an undergraduate in CAS, is working in Kelly Mayo’s lab. Elliot received an Endocrine Society summer fellowship for working on his project which involves the characterization of novel genes expressed in the ovary.

Joy Shen, an undergraduate biology student working with Fred Turek and Teresa Horton, was awarded a C.R.S. Go-to-Meeting award in order to attend the Society of Research on Biological Rhythms meeting in Jacksonville, FL in May 2000. She presented a poster entitled "Steroids modulate spatial learning in the Siberian hamster independently of photoperiod."

Susan Hood received her Ph.D. in June, 2000. Her advisor was Professor Emerita Neena Schwartz in Neurobiology and Physiology. The title of her thesis is "Sex Difference in Serum Luteinizing Hormone Post-Gonadectomy in the Rat: Involvement of Gonadotropin Releasing Hormone, Glutamate and Gamma-Aminobutyric Acid". One part of her thesis was just published in Endocrine: vol 12:35-40, 2000.

Sonali Anand, a graduate student in Fred Turek’s lab, was awarded First Prize in the student poster competition at the Sixth International Conference on Hormones, Brain and Behavior/Society for Behavioral Neuroendocrinology held in Madrid, Spain, August, 2000. Her poster was entitled "Social Stimulation of Luteinizing Hormone Secretion in Male Siberian Hamsters; Nature of the Stimulus and Potential Neural Pathways". Back to Top

CRS Go-To-Meeting Award for Undergraduates
A number of undergraduates at Northwestern work in the research laboratories of Center faculty. We have started a fund to enable some of them to attend professional meetings with their preceptors and other lab members. We invite applications for travel for the year 2000 meetings. Undergraduates should submit a letter outlining their research project and a description of the meeting to which they wish to go. They should also estimate the travel cost. Faculty advisors should countersign the documents. Please submit support documents to Dr. Neena Schwartz, Center for Reproductive Science, Hogan Hall, Evanston Campus.

Marcia L. Storch MD cholarship Fund for Undergraduate Women Before her death from ovarian cancer Dr. Marcia Storch expressed the wish that contributions be sent to the Center for Reproductive Science at Northwestern University to establish a fund to encourage undergraduate women to study the basic physiology and biochemistry to the ovary. With contributions we have received the Center invites applications from undergraduate women working in the laboratories of Center faculty. A committee will review the applications, which should include a brief description of project work and a statement from the advisor, and budget for supplies (not to exceed $400). Please submit supporting documents to Dr. Neena Schwartz, Center for Reproductive Science, Hogan Building, Evanston Campus. Back to Top

The placenta is the major endocrine organ of pregnancy, and in pregnancy hormones bring about very large and unusual changes in physiology. These dramatic changes occur in a carefully orchestrated manner in many physiological systems (metabolism, behavior, immune response, mammary development and milk production, etc.), and furthermore evolutionary pressure has ensured that these changes are both survivable and (for the most part) reversible. The analysis of the changes that occur during pregnancy provides an opportunity to find new and previously unsuspected mechanisms by which hormones regulate cell, tissue, and organ behavior. By identifying the factors which bring about these changes and by uncovering their means of action, it might be possible to exploit those discoveries to control physiology when it goes awry, from maintaining pregnancy when gestational problems arise, to using pregnancy-like changes to block pathophysiology. One series of experiments conducted by Dowdy Jackson and Daniel Linzer in the Department of Biochemistry, Molecular Biology, and Cell Biology, in collaboration with No�l Bouck and Olga Volpert, in the Department of Microbiology/Immunology, led to the discovery that two mouse placental hormones control the growth of blood vessels, a process critical both for normal reproduction and for pathologies such as cancer. More recently, Jiandie Lin, currently completing his graduate work, and Linzer have identified an important activity of another mouse placental hormone, Prolactin-Like Protein E or PLP-E.

PLP-E is a member of the cytokine superfamily, a group of regulatory proteins which mostly target blood cells. During pregnancy, blood cell production is significantly increased. The demands of the fetus for oxygen, and for disposal of carbon dioxide, result in increased maternal production of red blood cells. In addition, blood volume increases, bringing about a requirement for elevated production of blood platelets, essential in wound repair and blood clotting. Platelets are cell fragments which derive from megakaryocytes, and various cytokines act on megakaryocytes to stimulate their proliferation. PLP-E binds to a receptor present on megakaryocytes (see figure), and the addition of PLP-E to cells isolated from mouse bone marrow stimulates megakaryocyte differentiation. Furthermore, in combination with another cytokine, PLP-E treatment caused an increase in the number of megakaryocytes.

Although PLP-E is only made in the placenta, this hormone is able to bind to megakaryocytes from non-pregnant female mice and from male mice, suggesting that the PLP-E receptor may also be the target of other hormones under non-pregnant conditions. Receptor binding assays have revealed, though, that no other cytokine known to act on megakaryocytes shares the PLP-E receptor. Thus, the analysis of a placental hormone, PLP-E, may lead to the identification of a new cytokine receptor, and perhaps then to other currently unknown cytokines which share this receptor.

PLP-E also binds megakaryocytes in other species, including humans. Thus, the PLP-E regulatory system is broadly conserved. The detection of PLP-E binding to human megakaryocytes indicates that these cells express the PLP-E receptor even though humans do not appear to synthesize a protein resembling PLP-E. Mouse PLP-E may therefore prove to be a probe that will reveal a previously unrecognized cytokine/cytokine receptor system in humans. The human ligand for the PLP-E receptor may be important for megakaryocyte regulation during pregnancy. Humans and mice need to solve the same physiological problem, for which they may take advantage of the same regulatory pathway.

Megakaryocyte proliferation and differentiation, and platelet production, are also critical concerns in a number of human pathological conditions. In blood cell diseases, a common approach is to destroy all of the blood cells and start over using a new source of these cells from a donor’s bone marrow. This clinical method does work, but it also has many – often fatal – complications. Ideally, normal blood cells from the patient could be preserved before radiation is used to kill off all of the other blood cells, and then those few isolated cells could be expanded in the laboratory and transplanted back into the patient. In particular, blood cell preparations rich in megakaryocytes would be valuable to help patients recover the capacity to produce platelets, and to repair vascular damage. This type of autologous transplantation would eliminate the problem of matching a donor and recipient, but this theoretical goal is challenging because of the very limited growth potential of blood cells in culture at present.

To explore the idea that PLP-E might provide a clinically valuable activity, Lin and Linzer teamed up recently with Philip Lefebvre and Isaac Cohen in the Department of Medicine. Addition of PLP-E to human blood cell cultures was found to have significant effects that were not quite identical to those seen with mouse blood cells. Most importantly, PLP-E in conjunction with other cytokines stimulated the growth of precursor cells for both megakaryocytes and red blood cells. These results indicate that PLP-E may lead to the development of new combinations of cytokines which are even more effective at expanding a limited number of blood cells in culture, cells which can then be used to repopulate a patient’s blood system.

Jackson, D., Volpert, O., Bouck, N., and Linzer, D.I.H. 1994. Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science 266: 1581-1584.

Lin, J. and Linzer, D.I.H. 1999. Induction of megakaryocyte differentiation by a novel pregnancy-specific hormone. Journal of Biological Chemistry 274: 21485-21489.

Lin, J. and Linzer, D.I.H. 1999. A novel megakaryocyte differentiation factor from mouse placenta. Trends in Cardiovascular Medicine 9: 167-171.

Linzer, D.I.H. and Fisher, S.J. 1999. The placenta and the prolactin family of hormones - regulation of the physiology of pregnancy. Molecular Endocrinology 13: 837-840.

Lefebvre, P., Lin, J., Linzer, D.I.H., and Cohen, I. Prolactin-like protein E stimulates human myeloid precursor survival and expansion. (submitted)

Figure Legend
Adjacent mouse spleen sections were either incubated with PLP-E and stained for PLP-E binding (left) or stained directly for acetylcholinesterase (right), a marker for megakaryocytes. The arrows indicate cells that are positive for PLP-E and for acetylcholinesterase, demonstrating that PLP-E is binding specifically to megakaryocytes. (Figure adapted from Lin, J. and Linzer, D.I.H. 1999. Induction of megakaryocyte differentiation by a novel pregnancy-specific hormone. Journal of Biological Chemistry 274: 21485-21489.) Back to Top

Zheng, L., Sekerkora, G., Vranich, K., Tilney, L.G., Mugnaini, E. and Bartles, J.R. (2000) The deaf jerber mouse has a point mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and fails to accumulate espins. Cell (in press).

Murray, R.A., Maheshwari, H.G., Russell, E.J., Baumann, G. (2000) Pituitary hypoplasia in patients with a mutation in the growth hormone releasing hormone receptor gene. Am. J. Neuroradiol 21:685-689.

Podlasek, C., Seo, R., Clemens, J., Ma, L., Mass, R. and Bushman, W. (1999) Hox-a10 deficient mice exhibit abnormal development of male sex accessory organs. Developmental Dynamics 214:1-12.

Li, S., Liang, Z-G., Wang, G-Y., Yavetz, B., Kim, E.D. and Goldberg, E. (2000) Molecular cloning and characterization of functional domains of a human testis-specific isoform of calpastatin. Biol Reprod 63:172-178.

Bernard, D.J., Merzylak, I.Y., Horton, T.H. and Turek, F.W. (2000) Differential regulation of pituitary gonadotropin subunit messenger ribonucleic acid levels in photostimulated Siberian hamsters. Biol Reprod 62:155-161.

Mukherjee, S., Gurevich, V.V., Jones, J.C.R., Casanova, J.E., Frank, S.R., Maizels, E.T., Bader, M-F, Khan, R.A., Palczewski, K., Aktories, K. and Hunzicker-Dunn, M. (2000) The ADP ribosylation factor nucleotide exchange factor ARNO promotes barrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization. Proc Natl Acad Sci 97:5901-5906.

Matthews E. Yang T, Janulis L, Goodwin S, Kundu SD, Karpus WJ and Lee C. (2000) Down regulation of TGF$1 production restores immunogenicity in prostate cancer cells. British Journal of Cancer (in press).

Xu, M., Urban, J., Danforth, J. and Levine, J.E. (2000) Regulation of neuropeptide Y1 receptor gene expression during the estrous cycle: role of progesterone receptors. Endocrinology 141:3319-3327.

Ma, G.T. and Linzer, D.I.H. (2000) GATA-2 restricts prolactin-like protein A expression to secondary trophoblast giant cells. Biol Reprod (in press).

Ito, M., Park, Y., Weck, J., Mayo, K.E. and Jameson, J.L. (2000) Synergic activation of the inhibin ‘ subunit promoter by steroidogenic factor-1 and cAMP. Molecular Endocrinology 14:66-81.

Szabo, M., Kilen, S.M., Nho, J. and Schwartz, N.B. (2000) Progesterone receptor A and B messenger ribonucleic acid levels in the anterior pituitary of rats are regulated by estrogen. Biol Reprod 62:95-102.

Sciarra, J.J. (2000) FIGO and the IJGO begin the new millenium. Int J Gynecol Obstet 68:1-2.

Phillip L. Lowrey, Kazuhiro Shimomura, Marina P. Antoch, Shin Yamazaki, Peter D. Zemenides, Martin R. Ralph, Michael Menaker, Joseph S. Takahashi (2000) Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288:483-491.

Chen, W., Woodruff, T.K. and Mayo, K.E. (2000) Activin A-induced HepG2 liver cell apoptosis: involvement of activin receptors and Smad proteins. Endocrinology 141:1263-125.

Chong, H., Pangas, S., Bernard, D., Wang, E., Gitch, J., Chen, W., Draper, L., Cox, E. and Woodruff, T.K. (2000) Structure and expression of a membrane component of the inhibin receptor system. Endocrinology 141:2600.

Rudick, C.N. and Woolley, C.S. (2000) Estradiol induces a phasic c-Fos response in the hippocampus of adult female rats. Hippocampus 10, pp. 274-283.