Research Spotlight


Cathy K. Naughton, M.D.
Assistant Professor
Division of Urologic Surgery, Department of Surgery
Director of Male Infertility and Microsurgery
Washington University School of Medicine


The Role of Ret in Spermatogenesis

Editor's Note:
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.

A family 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.

  1. The 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.

  2. 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.

  3. 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 examined.

  4. 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.