Patricia A. DeLeon, Ph.D.

Teaching

  • BISC 105 - Human Heredity and Development
  • BISC 492 - Human Molecular Cytogenetics
  • BISC 693 - Human Molecular Genetics (Syllabus)
  • BISC 693 - Human Molecular Genetics (Schedule)

Research Interests

On the left is seen an infertile transgenic sperm with overexpressed Spam1 located in a cytoplasmic droplet (double arrow) on the tail. On the right a wild type sperm is seen with Spam1 in the normal location on the head (single arrow).

The identification of genes and mechanisms that are involved in sperm dysfunction and male factor infertility/subfertility is the focus of our laboratory. We are interested in candidate or novel genes that play a role in spermatogenesis, epididymal sperm maturation, and fertilization. The latter can be considered as the process by which the genome passes from one generation to the next. Not only is the laboratory interested in the function of the genes and their impact on male germ cell differentiation, but also in their regulation (transcriptional and posttranscriptional). Thus our interest lies in the genetic and molecular mechanisms of spermatogenesis, epididymal function, and the molecular aspects of fertilization.

One class of genes being currently studied is the mammalian hyaluronidases which are abundantly expressed in the testis. There are seven family members of these genes and they are tightly linked in two clusters on different chromosomes. The best studied of these is the Sperm Adhesion Molecule 1 (SPAM1) which is widely conserved, being found in every mammalian species that has been studied to date. SPAM1 encodes a sperm membrane glycosyl phosphatidylinositol- (GPI)-linked protein (SPAM1 or PH-20) which plays multiple essential roles in fertilization. These include cumulus penetration, zona pellucida binding, and hyaluronic acid receptor activity during the signal transduction involved in acrosomal exocytosis. We are interested in determining if all the hyaluronidase genes have unique or overlapping functions, or if they operate as a classical polygenic system.

Current Projects

  • Posttranscriptional Regulation of Spam1 - Spam1 is abundantly expressed in round spermatids and transcription levels off in elongated spermatids. Similar to other spermatid-expressed genes, for SPAM1 the condensation of the chromatin during the transformation of the round spermatid into a polarized cell results in premature termination of transcription. Thus there is a heavy reliance on posttranscriptional regulation. We are investigating the posttranscriptional regulation of expression of the murine Spam1 as a model for spermatid-expressed genes. The hypothesis that testicular Spam1 is regulated by cis-acting AU-rich elements (AREs) in the 3'UTR which recognize RNA-binding proteins and which are modulated by antisense transcription is being tested.
  • The basis of sperm infertility following Spam1 overexpression and the retention of cytoplasmic droplets - Transgenic overexpression of murine Spam1 leads to abnormal spermiogenesis which results in the retention of cytoplasmic droplets (CDs), organelles which are present on the flagellum and which are generally associated with sperm infertility in mammals. The CDs resulting from Spam1 overexpression are engorged with Spam1 which is absent from the sperm head, the normal location. Our overall hypothesis is that the infertility of these sperm results partly from their reduced motility as well as the absence of hyaluronidases on the heads. Studies to test several hypotheses related to this overall hypothesis are being investigated.
  • SPAM1 overexpression and Metastatic cancer - Overexpression of SPAM1 is also associated with a variety of cancers in both reproductive and non-reproductive organs. The transcript, normally present in low abundance in these non-testicular tissues, is upregulated and detectable by Northern analysis during tumor progression. Our discovery of the ARE-mediated stabilization of Spam1 RNA allows us to hypothesize that trans-acting RNA-binding proteins are involved in the upregulation of the RNA and the ensuing cancer progression. Understanding the molecular mechanisms involved in the upregulation is key to developing therapeutic strategies to overcome the disease, and studies are proposed to identify the proteins involved.
  • The Mechanism of Cross-talk between Spam1 and related Hyaluronidases - Our findings have suggested that there is cross-talk between members of the hyaluronidase family members. Using double null mice, experiments have been designed to verify whether or not there is cross-talk between Spam1 and Hyal5 as well as other hyase family members; and how the cross-talk may be modulated, specifically with respect to antisense RNA. The latter has been detected for Spam1. The antisense regulation of these genes could serve as a model for spermatid-expressed gene families.
  • The Mechanism of Sperm uptake of Epididymal Spam1 - Our lab was the first to discover the expression of Spam1 in the extratesticular pathway (the efferent duct, the epididymis and the vas deferens) as well as the female tract. We have also shown that in these organs Spam1 is secreted in the luminal fluid in a form in which it can be taken up by sperm. Recently, we have shown the in vitro uptake of luminal Spam1 by sperm and are currently determining the mechanism by which the binding occurs on the sperm plasma membrane.
  • The Role of JAM-A in Ca2+ Clearance in Sperm - Another sperm membrane protein in which our lab is interested is Junctional Adhesion Molecule A (JAM-A) which is known to regulate tight junction integrity, and is present between the Sertoli cells that maintain the blood testis barrier. Our lab discovered its presence in human and mouse sperm and showed that its absence results in elevated Ca2+ levels, decreased ATP levels, and reduced sperm motility. Further, we have shown that JAM-A interacts with the Ca2+ extrusion pump (PMCA4) and Ca2+ serine kinase (CASK). Studies are proposed to document this interaction and determine how deletion of Cask might affect the tripartite protein complex, the function of the pump, and sperm motility.

Research Group

  • Amal Aldossary, M.A.
  • Rachel Andrews, B.A.
  • Kathie Wu - Undergraduate researcher.
  • Rebecca Pollak - Undregraduate researcher.
  • Ramkrishna Patel - Undergraduate Researcher. Post-testicular Expression of PMCA4.
  • Emily Jacobson - Undergraduate Researcher. The regulation of Nitri Oxide in sperm.

Selected Publications

Trustees Distinguished Professor
2007 U.S. Presidential Awardee
Faculty Representative to the Board of Trustees

Phone: (302) 831-2249

Fax: (302) 831-2281

Email: pdeleon@udel.edu

Office: 219 McKinly Lab

Lab: 265/267 McKinly Lab

Address:
Department of Biological Sciences
Wolf Hall
University of Delaware
Newark, DE 19716

Education

  • B.Sc. (Hons.), M.Sc. - University of the West Indies (Jamaica)
  • Ph.D. - University of Western Ontario (Canada)
  • Postdoctoral - McGill University (Canada)