Featured SMRU MEMBER:
Cathy K. Naughton, M.D.
Division of Urologic Surgery, Department of
Director of Male Infertility and Microsurgery
University School of Medicine
Role of Ret in Spermatogenesis
The SMRU Board believes that we as an organization should
support our colleagues engaged in basic science or clinical research. We will
thus periodically feature colleagues and their work in this section of the web
site. We hope that this column will help promote collaborative efforts and
improved awareness of the research activities of our members. Cathy Naughton,
M.D. is featured in this segment. Cathy completed fellowship training with
Anthony J. Thomas, Jr., M.D. at the Cleveland Clinic and subsequently assumed an
academic position in the Department of Urology at Washington University in St.
Louis. She details her basic science interests below.
of neurotropic factors [glial cell line-derived neuotrophic factor (GDNF) and
its related receptors] which utilizes Ret receptor tyrosine kinase-mediated
signaling, is important in the nervous system for cell survival, proliferation,
and differentiation. Ret-mediated signaling has recently been implicated to have
a non-neuronal role in the developing reproductive system. My interest in the
role of these neurotropic factors in testicular development, spermatogenesis,
and tumorigenesis has resulted in collaboration with Jeffrey Milbrandt, MD, PhD,
Professor of Pathology and Internal Medicine.
Our hypothesis is that
glial cell line-derived neurotrophic factor (GDNF) and Ret-mediated signaling is
critical for normal spermatogenesis. Previous studies suggest that appropriate
GDNF expression in the testis is necessary for normal sperm survival,
proliferation, and/or maturation; and, that accumulation of sperm precursors,
resulting in germ cell tumors. We are pursuing several projects to establish the
role of Ret signaling in the spermatogenesis.
expression of studies of Ret, GDNF, and GFRα1. We are studying the
expression patterns of these factors by using knockout/knockin mouse models in
combination with cell and stage specific markers to determine when and where
these factors are expressed in the first wave of mouse spermatogenesis.
Testicular phenotypes of Ret mutant mice. We have
generated multiple mouse lines of the two isoforms of Ret along with various
mutations to the tyrosine residues known to be important in Ret signaling. By
examining the testicular phenotypes of mutant mouse lines, we will determine
which Ret isoform is critical for normal spermatogenesis.
Testicular transplantation. We are utilizing the
technique of whole testicular tissue transplantation to study postnatal
spermatogenesis of perinatal lethal mutant mice. As Ret, GDNF, and
GFRα1 knockout animals all die several hours after birth, the
importance of these genes in postnatal spermatogenesis has not been previously
Microsurgical injection of mouse testicular
efferent ducts. This technique will be used for future in vivo rescue
experiments of mouse lines with abnormal testicular spermatogenesis and
testicular stem cell transplantation experiments.
Significance of Research
As Director of Male
Infertility and Microsurgery, my clinical practice is dedicated to the
management and treatment of male-factor infertility. Approximately 60% of my
patients who present with azoospermia (no sperm in the ejaculate) suffer from
abnormal spermatogenesis, resulting in testicular failure. The molecular
mechanisms responsible for the histological diagnoses of hypospermatogenesis,
maturation arrest, and Sertoli-cell only are not known. Presently, the only
available option for possible biological pregnancy for these couples is in-vitro
fertilization with intracytoplasmic sperm injection. Our efforts will determine
the role of Ret-mediating signaling in mouse spermatogenesis to gain better
understanding of the molecular mechanism responsible for clinical testicular
failure. This is the first step in developing potential therapeutic strategies
in men with non-obstructive azoospermia.