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Dr. Patricia A. DeLeon
Professor
Faculty Representative to the Board of Trustees
Contact
DeLeon
Office: 219 McKinly Lab
Lab: 265/267 McKinly Lab
Mailing address:
Department of Biological Sciences
Wolf Hall
University of Delaware
Newark, DE 19716
Phone: (302) 831-2249
Fax: (302) 831-2281
E-mail: pdeleon@udel.edu
Education
B.Sc.(Hons): University of the West Indies, Jamaica
M.Sc.: University of the West Indies, Jamaica
Ph.D.: University of Western Ontario, Canada
Postdoctoral: McGill University, Canada
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 Spermatogenesis - Another testicular membrane protein in which our lab is interested is Junctional Adhesion Molecule A (JAM-A) discovered and characterized in Dr. Ulhas Naik's laboratory. JAM-A has been shown to regulate tight junction integrity and cell polarity. Evidence suggests that tight junctions of Sertoli cells that maintain the blood testis barrier might be disrupted in its absence which is associated with male subfertility. Studies are proposed to document the subfertility, characterize testicular expression and associated Sertoli-Sertoli cell tight junction, and perform transgenic rescue of the subfertility in JAM-A null mice.
Teaching
- BISC 105 - Human Heredity and Development
- BISC 492 - Human Molecular Cytogenetics
- BISC 693 - Human Molecular Genetics
Research Group
- Rolands Aravindan, Ph.D. - Postdoctoral Fellow (Ph.D., National Dairy Research Institute, India). Mutations involved in Sperm motility.
- Minghai Shao, Ph.D. - Postdoctoral Fellow (Ph.D., Chinese Academy of Sciences, China). The role of JAM-A in sperm motility.
- Genevieve Griffiths, B.A. - Graduate Student (B.A., University of Delaware). Mechanisms of uptake of GPI-linked proteins.
- Laura Falconieri - Undergraduate. Cross talk between murine hyaluronidases.
- Rowan Michael - Undergraduate. Mechanisms involved in retention of excess cytoplasm in sperm.
Vacancies exist in our lab graduate students interested in pursuing studies in the following two graduate programs in our department: Molecular Biology and Genetics, Cell and Extracellular Matrix Biology, and Animal Physiology. Outstanding graduate students are eligible to apply to the IGERT fellowship program and for stipend under the CBI (Chemistry-Biology Interface) program.
Selected Publications
Griffiths, G.S., Miller K.A., Galileo D.S., Martin-DeLeon, P.A.: SPAM1 is secreted by the estrous murine uterus and oviduct in a form which can bind to sperm during capacitation: Acquisition enhances hyaluronic acid-binding ability and cumulus penetration efficiency. Reproduction 135:1-10 (2007).
Shao M., Ghosh A., Cooke V.G., Naik U.P., Martin-DeLeon, P.A.: JAM-A is present in Mammalian Spermatozoa where it is Essential for Normal Motility. Dev Bio. (2007) doi:10.1016/j.ydbio.2007.10.013.
Grigorieva A., Griffiths G.S., Zhang H., Laverty G., Shao M., Taylor L., Martin-Deleon P.A.: Expression of SPAM1 (PH-20) in the Murine Kidney Is Not Accompanied by Hyaluronidase Activity: Evidence for Potential Roles in Fluid and Water Reabsorption. Kidney Blood Press Res. 30:145-155 (2007).
Miller K.A., Shao M., Martin-DeLeon P.A.: Hyalp1 in Murine Sperm Function: Evidence for Unique and Overlapping Functions with Other Hyaluronidases. J Androl. 28:67-76 (2007).
Chen H., Griffiths G.S., Galileo D.S., Martin-DeLeon P.A.: Epididymal SPAM1 is a marker of Sperm Maturation in Mouse. Biol Reprod. 74:923-930 (2006).
Martin-DeLeon P.A.: Epididymal Spam1 and its impact on Sperm Function. Mol Cell Endocrinol. 250:144-121 (2006).
Zhang H., Barnoski B.L., Sol-Church K., Stabley D., Martin-DeLeon P.A.: Murine Spam1 mRNA: Involvement of AU-rich elements in the 3'UTR and antisense RNA in its tight posttranscriptional regulation in Spermatids. Mol Reprod Dev. 73:247-255 (2006).
Martin-DeLeon P.A., Zhang H., Evans E.A., Jones R., Morales C.R., Grigorieva A.: SPAM1 (PH-20) Expression Along the mammalian Male reproductive tract, the accessory organs and the kidney: Evidence for Multiple roles in the Extratesticular pathways. In Hyaluronan: Structure, Metabolism, Biological Activities, therapeutic Applications, E.A. Balazs and V.C. Hascall eds., p 229-234, 2005; Matrix Biology Inst., N.J.
Martin-DeLeon P.A., Zhang H., Morales C.R., Zhao Y., Rulon M., Barnoski B.L., Chen H., Galileo D.S.: Spam1-Associated Transmission Ratio Distortion in mice: elucidating the mechanism. Reprod Biol Endocrinol. 3:32 (2005).
Zhang H., Shertok S., Miller K., Taylor L., Martin-DeLeon, P.A.: Sperm Dysfunction in the Rb(6.16)- and Rb(6.15)-bearing mice revisited: Involvement of Hyalp1 and Hyal5. Mol Reprod Dev. 72:404-410 (2005).
Zhang H., Morales C.R., Badran H., El-Alfy M., Martin-DeLeon P.A.: Spam1 (PH-20) Expression in the Extratesticular Duct and Accessory Organs of the Mouse: A Possible Role in Sperm Fluid Reabsorption. Biol Reprod. 71:1101-1107 (2004).
Morales C.R., Badran H., El-Alfy M., Men H., Zhang H., Martin-DeLeon P.A.: Cytoplasmic Localization During Testicular Biogenesis of the Murine mRNA for Spam1 (PH-20), a Protein Involved in Acrosomal Exocytosis. Mol Reprod Dev. 69:475-482 (2004).
Zhang H., Jones R., Martin-DeLeon P.A.: Expression and secretion of rat Spam1 (2B1 or PH-20) in the epididymis: Role of testicular lumicrine factors. Matrix Biol. 22:653-661 (2004).
Zhang H. and Martin-DeLeon P.A.: Mouse epididymal Spam 1 (PH-20) is released in the luminal fluid with its lipid anchor. J Androl. 1:51-58 (2003).
Zhang H. and Martin-DeLeon P.A.: Mouse Spam1 (PH-20) is a multifunctional protein: Evidence for its expression in the female tract. Biol Reprod. 69:446-454 (2003).
Evans E.A., Zhang H., Martin-DeLeon P.A.: Spam1 protein and mRNA expression in the epididymides of humans and macaques: Utilizing laser microdissection/RT-PCR. Reprod Biol Endocrinol. 1:54 (2003).
Zhang H. and Martin-DeLeon P.A.: Mouse epididymal Spam1 (PH-20) is released in vivo and in vitro, and Spam1 is differentially regulated in testis and epididymis. Biol Reprod. 65:1586-1593 (2001).
Martin-DeLeon P.A., Piumi F., Rogel-Gaillard C., Hendy G.N.: Assignment of the parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR1) to rabbit chromosome band 9p14-->p13 by fluorescence in situ hybridization. Cytogenet Cell Genet. 94:90-91 (2001).
Zheng Y., Deng X., Zhao Y., Zhang H., Martin-DeLeon P.A.: Spam1 (PH-20) mutations and sperm dysfunction in mice with the Rb(6.16) or Rb(6.15) translocation. Mamm Genome. 12:822-829 (2001).
Zheng Y., Deng X., Martin-DeLeon P.A.: Lack of sharing of Spam1 (Ph-20) among mouse spermatids and transmission ratio distortion. Biol Reprod. 64:1730-1738 (2001).
Deng X., He Y., Martin-DeLeon P.A.: Mouse Spam1 (PH-20): evidence for its expression in the epididymis and for a new category of spermatogenic-expressed genes. J Androl. 21:822-832 (2000).
Zheng Y., Martin-DeLeon P.A.: Characterization of the genomic structure of the murine Spam1 gene and its promoter: evidence for transcriptional regulation by a cAMP-responsive element. Mol Reprod Dev. 54:8-16 (1999).
Zheng Y., Martin-DeLeon P.A.: The murine Spam1 gene: RNA expression pattern and lower steady-state levels associated with the Rb(6.16) translocation. Mol Reprod Dev. 46:252-257 (1997).
Deng X., Moran J., Copeland N.G., Gilbert D.J., Jenkins N.A., Primakoff P., Martin-DeLeon P.A.: The mouse Spam1 maps to proximal chromosome 6 and is a candidate for the sperm dysfunction in Rb(6.16)24Lub and Rb(6.15)1Ald heterozygotes. Mamm Genome. 8:94-97 (1997).
Nagle D.L., Martin-DeLeon P.A., Hough R.B., Bucan M.: Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H Rw on mouse chromosome 5. Proc Natl Acad Sci USA. 91:7237-7241 (1994).
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