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Newsletter
A publication of the Center for Reproductive Science
Northwestern University, Evanston and Chicago
Fall 1999 Volume 1 No. 1
In This Issue:
From the Director
Seminars
Marcia L. Storch MD Scholarship Fund for Undergraduate Women
Faculty & Interest Areas
Recent Ph.D. Graduates
CRS Go-to-Meeting Travel Award for Undergraduates
A Tail of Mouse & Man
Recent Publications
From the Director
W e are grateful to Vice President for Research Lydia Villa-Komaroff
for providing the Center with funds to initiate a newsletter this year. We hope to bring
you news of the research of members of the center, as well as information for students and
other members of the Northwestern community about joining our sponsored educational and
research programs. The Northwestern University Center for Reproductive Science began as a
program in 1977 and became a center in 1987. The Center carries out many activities
designed to enhance the teaching and research missions of its faculty. The faculty is
highly multidisciplinary and consists of both basic and clinical scientists on the
Evanston and Chicago campuses.
The Center sponsors an annual Minisymposium in the fall of each year,
featuring trainee papers, prizes for the best oral and poster presentations as well as an
outside speaker: the roster of outside speakers from past years is a virtual Who’sWho
of reproductive science, including Jack Gorski, Bert O’Malley, Sue Smith, Michael
Conn and Wylie Vale. The speaker for the 20th
Symposium, in October, 1999 was Professor Phyllis Wise, Chair of the Department of
Physiology at the University of Kentucky Medical School, who will speak on
"Neuroendocrine contributions and repercussions of the menopause: a window to the
aging of the brain". The Center also sponsors a series of seminars held mostly on the
Evanston campus, which are listed on this page.
We are also developing a web-page at
<http://x.biochem.nwu.edu/crs.html>. Check it out!
Research in reproduction lends itself particularly well to
collaborative, interdisciplinary interactions and the Center provides an excellent mechanism for fostering these interactions. A list of recent
publications of center members will be included in each issue. A summary of some recent
research by Gerry Baumann of the Department of Medicine and Kelly
Mayo in BMBCB can be found on page 3 of the current issue.
Remember- with growing concern about an increasing world population and
a deteriorating environment
——-reproduction matters!
Neena Schwartz, Director
r
Seminars
11/02/99 Dr. Christin Carter-Su, University of Michigan - 4:00
p.m., Chicago Campus
02/01/00 Dr. Kimberly Mowry, Department of Molecular Biology,
Cell Biology, and Biochemistry, Brown University, Providence RI "RNA
Localization in Xenopus Oocytes" - 4:00 p.m., Ward Building, Chicago Campus
02/07/00 Dr. Holly Ingraham, UCSF - 4:00 p.m., Evanston
Campus
03/13/00 Dr. Ok Kyong Park-Sarge, University of Kentucky - 4:00
p.m., Evanston Campus
04/04/00 Dr. David Albertini, Tufts University (CMB Department
speaker) - 12:00 noon, Evanston Campus
05/01/00 Dr. David Schomberg, Duke University - 4:00 p.m.,
Evanston Campus
10/16/00 Dr. Jeffrey Rosen, Baylor College of Medicine (Keynote
speaker at the mini-symposium)
Awards for Undergraduate Research
Marcia L. Storch MD Scholarship Fund for Undergraduate Women
Dr. Marcia Storch, who practiced gynecology in New York City and taught
at several medical schools, died on November 9, 1998. She was widely regarded as a pioneer
and innovator in women’s health care. Her obituary in the New York Times (11/19/98)
described her thus. "Dr. Storch was born in Pittsburgh. She graduated from Bryn Mawr
College and the Medical College of Pennsylvania. In 1971 she moved to New York City. She
directed the Adolescent Gynecology and Family Planning Clinic at St. Luke’s-Roosevelt
Hospital Center, which provided treatment as well as information on birth control and
sexually transmitted diseases to tens of thousands of disadvantaged teenagers. After her
retirement from private practice in 1989, she sought a wider audience for her approach to
medicine as a television and radio producer. She created specialized programming for
family physicians on the Lifetime medical network, and later became the head of Ob/Gyn
news for the Medical News Network".
Before her death from ovarian cancer Dr. Storch expressed the wish that
contributions be sent to the Center for Reproduction Science at Northwestern University to
establish a fund to encourage undergraduate women to study the basic physiology and
biochemistry of 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 projected 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 Sciences, Hogan Building, Evanston Campus.
Donations continue to be accepted for this fund. Checks should be made
out to the Center for Reproductive Science and directed to the "Marcia Storch
Scholarship Fund".
Congratulations to Recent Graduates
Abir Mukherjee
(with Kelly Mayo) "Regulation of Inhibin Alpha Subunit Gene Expression by the
Gonadotropins in Rat Ovarian Granulosa Cells" |
Carl Albert Peters
(with Mary Hunzicker-Dunn) "Regulation of PKC Delta in the Pregnant Rat Corpus
Luteum; Involvement in the Induction of Relaxin Expression" |
Pat Chappell
(with Jon Levine) "The role of hypothalamic progesterone receptors in initating
gonadotropin surges" |
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CENTER FOR REPRODUCTIVE SCIENCE
FACULTY & INTEREST AREAS
Testis Function
James Bartles, Cell & Molecular Biology
Erwin Goldberg, Bio Chem Mol & Cell Biology
Richard Scarpulla, Cell & Molecular Biology
Pituitary Function
J. Larry Jameson, Medicine
Neena Schwartz, Neurobiology & Physiology
Jeffrey Weiss, Medicine
Circadian Rhythms
Joseph Takahashi, Neurobiology & Physiology
Fred Turek, Neurobiology & Physiology
Teresa Horton, Neurobiology & Physiology
Neural Control of Sexual Function
Kevin McKenna, Physiology
Prostate Biology
Chung Lee, Urology
Juila Sensibar, Urology
Zhou Wang, Urology
Wade Bushman, Medical Urology
Neuroendocrinology
George Flouret, Physiology
Jon Levine, Neurobiology & Physiology
Eva Redei, Psychiatry & Behavioral Science
Catherine Woolley, Neurobiology & Physiology
Clinical Fertility & Infertility
Ralph Kazer, Obstetrics & Gynecology
John Sciarra, Obstetrics & Gynecology
Growth & Development
Gerhard Baumann, Medicine
Daniel Linzer, Bio Chem Mol & Cell Biology
Kelly Mayo, Bio Chem Mol & Cell Biology
Elizabeth Puscheck, Obstetrics & Gynecology
Daniel Rappolee, Cell & Molecular Biology/Obstetrics & Gynecology
H. William Schnaper, Pediatrics
Andrew Shenker, Pediatrics
Ovarian Function
Robert Chatterton, Obstetrics & Gynecology
Mary Hunzicker-Dunn, Cell & Molecular Biology
Teresa K. Woodruff, Medicine/NBP
Steroid Hormones & Receptors
Magdy Milad, Obstetrics & Gynecology
CRS - RESEARCH NOTES
Mutation in the Growth Hormone Releasing Hormone Receptor Gene-A Tail of
Mouse and Man
Two members of the Center for Reproductive Science, Gerry Baumann of
the Department of Medicine in Chicago and Kelly Mayo, Department of BMBCB in
Evanston, have made major contribution to the understanding of the regulation of growth in
man and mouse. The synthesis and secretion of growth hormone (GH) in the anterior
pituitary gland is controlled by neuropeptides from the hypothalamus, including the
stimulatory hormone growth hormone-releasing hormone GHRH) and the inhibitory hormone
somatostatin. These hormones bind to G protein-coupled receptors to modulate the activity
of adenylate cyclase and the production of cAMP in the pituitary GH-secreting or
somatotroph cell. In addition to its effects on GH secretion, GHRH functions as a trophic
factor, stimulating proliferation of the somatotroph cell. Following the identification of
GHRH, it was proposed that deficiencies in GHRH production or action might provide a
logical explanation for some types of human heritable isolated growth hormone deficiency.
In 1992, Mayo identified a specific receptor for GHRH that
mediates GHRH actions on the somatotroph. In collaboration with Drs. Jenkins and Copeland
at the National Cancer Institute the receptor gene was mapped to a region of mouse
chromosome 6 that included the gene mutated in the little mice. The autosomal
recessive little mutation, discovered in 1976 at the Jackson Laboratories, causes a
profound deficiency in growth hormone leading to a dwarf phenotype. In collaboration with
Dr. Wesley Beamer of the Jackson Laboratory, Mayo subsequently demonstrated that the GHRH
receptor of the little mouse harbored a missense mutation in which a highly
conserved aspartic acid at position 60 in the amino-terminal extracellular domain of the
receptor is changed to glycine. This mutant receptor is unable to bind GHRH, leading to
the observed growth hormone deficiency and dwarfism.
In 1984, a newspaper article in Karachi, Pakistan reported on a newly discovered
cluster of dwarfs in two remote villages in the province of Sindh, Pakistan under the
heading "The dwarfs of Sindh". Dr. H. Maheshari, then residing in Karachi,
contacted Baumann with the proposal to determine the cause of this apparently
familial dwarfism. Thus started a long collaboration that culminated in the discovery of a
new form of isolated growth hormone (GH) deficiency due to a nonsense mutation in the
growth hormone releasing hormone (GHRH) receptor gene, and its detailed phenotypic
description based on 18 identified patients. The Pakistani kindred affected by dwarfism
exhibits a high degree of consanguinity. The disorder is inherited in an autosomal
recessive mode; it is caused by a point mutation in the extracellular domain of the GHRH
receptor that converts a glutamic acid to stop codon. As a consequence, the receptor is
totally dysfunctional and probably nonexistent.
In its homozygous form, the mutation causes severe postnatal GH
deficiency and pituitary (stomatotroph) hypoplasia. Adult men average 129 cm, adult men
average 129 cm, adult women 113 cm in height - 7-8 standard deviation below the norm.
There is no response to GH secretagogues, and insulin-like growth factor 1 (IGF-1) levels
are extremely low. Heterozygotes have subnormal GH and IGF-1 levels but a near-normal
physical phenotype. Other than GH-deficient dwarfism and relative microcephaly, affected
patients are phenotypically normal. They exhibit proportionate dwarfism with near-perfect
miniaturization devoid of any dysmorphic aspects. Pituitary and endocrine functions other
that the GH axis are normal.
This new syndrome is the human homologue of the little mouse.
Independent of this Pakistani kindred, 2 patients with the identical mutation have been
described in New York, and 2 others in Paris. All originate on the Indian subcontinent and
are probably related, albeit distantly. In addition, a large kindred with a different
(splice site) mutation in the GHRH receptor has recently been identified in Brazil. These
new discoveries may lead to the identification of milder mutations or polymorphisms in the
GHRH receptor gene as the basis for milder forms of familial short stature.
The rapid translation of basic research information into the clinic promises to enhance
the diagnosis and treatment of basic research information into the clinic promises to
enhance the diagnosis and treatment of syndrome of growth hormone deficiency and growth
excess. In turn, the large numbers of naturally occurring mutations in transcriptional
regulatory proteins and signal transduction proteins of the growth hormone axis in human
disease promise to provide a wealth of new information that will enhance our basic
understanding of the structure and function of these key regulatory proteins.
| CRS Go-to-Meeting Travel
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 supporting documents to Dr. Neena
Schwartz, Center for Reproductive Science, Hogan Hall Evanston campus. |
RECENT PUBLICATIONS
Achermann, J.C., Ito, M., Hindmarsh, P.C., and Jameson, J.L.
(1999) A mutation in gene encoding steroidogenic factor-1 causes XY sex-reversal and
adrenal failure in humans. Nat. Genet. 22:125-126.
Ambhaikar, M. and Goldberg, E. (1999) DNA protein interactions
in the CCAAT box region of the murine lacate dehydrogenase C promotor. Mole. Reprod.
Devel. 52:360-365.
Chappell, P.E., Schneider, J.S., Kim, P., Xu, M., Lydon, J.P.,
O’Malley, B.W., and Levine, J.E. (1999) Absence of gonadotropin surges and
gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E 2)-treated, progestrone receptor knockout (PRKO) mice. Endocrinology
140:3653-3658.
Frias, A.E., Li, H., Keeney, G.L., Podratz, K.C., and Woodruff, T.K.
(1999) Preoperative serum levels of inhibin A is a independent prognostic factor for the
survival of postmenopausal women epithelial ovarian carcinoma. Cancer 85:465-471.
Maheshwari, H.G., Rahim, A., Shaler, S.M., and Baumann, G.
(1999) Selective lack of growth hormone (GH) response to the GH-releasing
peptide hexarelin in patients with GH-releasing hormone receptor deficiency. J. Clin.
Endocrinol. Metab. 84:956-959.
Miller, T.L., Godfrey, P.A., DeAlmeida, V., and Mayo, K.E.
(1999) The rat growth hormone-releasing hormone receptor gene: Structure, regulation and
generation of receptor isoforms with different signaling properties. Endocrinology 140:
4152-4165.
Mukherjee, S., Palczewski, K., Gurevich, V., Benovic, J.L., Banga, P.,
and Hunzicker-Dunn, M. (1999) A Direct role for arrestins in desensitization of the
luteinizing hormone/choriogonadotopin-receptor in porcine ovarian follicular membranes. Proc.
Natl. Acad. Sci. 96:493-498.
Müller, T.L., Gondos, B., Kosugi, S., Mori, T., Shenker, A.
(1998) Severe testotoxicosis phenotype associated with asp578 Tyr mutation of the
lutropin/choriogonadotropin receptor gene. J. Med. Genet. 35:340-341.
Pewitt, E.B., Haleem, R., and Wang, Z. (1999) Andrenomedullin
gene is abdundantly expressed and directly regulated by andorgen in the rat ventral
prostate. Endocrinology 140:2382-2386.
Schwartz, N.B., Szabo, M. Verina, T., Wei, J.J., Dlouhy, S., Won,
L., Heller, A., Hodes, M.E., and Ghetti, B. (1998) The hypothalamic-pituitary gonadal-axis
in the mutant weaver mouse. Neuroendocrinology 68:374-385.
Sintich, S.M., Lamm, M.L.G., Sensibar, J.A., and Lee, C. (1999)
Transforming growth factor-ß 1 induced proliferation of the prostate cancer cell line,
TSU-Pr1: the role of platelet-derived growth factor. Endocrinology 140:3411-3415.
Toft, D.J., and Linzer, D.I.H. (1999) Prolactin-like protein J,
a novel member of the prolactin/growth hormone family, is exclusively expressed in
maternal decidua. Endocrinology in press.
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