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Patricia A. DeLeon, Ph.D.
- BISC 105 - Human Heredity and Development
- BISC 403 - Genetics and Evolutionary Biology
- BISC 492 - Human Molecular Cytogenetics
- BISC 693 - Human Molecular Genetics (Syllabus)
- BISC 693 - Human Molecular Genetics (Schedule)
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.
The Role of PMCAs in integrating Ca2+ and Nitric Oxide (NO) Signaling in Sperm
Plasma membrane Ca2+-ATPases (PMCAs) are a family of 4 ubiquitously expressed Ca2+ efflux pumps. They are transmembrane proteins that are encoded by 4 genes unclustered in the genome. Due to alternative splicing there are ~30 PMCA pumps which are differentially expressed in the tissues. In the testis PMCA4 and PMCA1 are expressed and are found in sperm in the ratio of 9:1. These efflux pumps are also expressed in the epididymal, uterine, and oviductal fluids where they are found in exosomes which are capable of delivering them to sperm amid other molecules in their cargo. Our Lab is studying the mechanism(s) by which these transmembrane proteins are delivered to the sperm membrane via the exosomes, as well as the mechanism by which targeted deletion of Pmca4 in mice leads to loss of sperm motility (asthenozoospermia) and male infertility.
- Reproductive Exosomes and the Transfer of Fertility-Modulating Proteins to Sperm during Their Maturation - 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 shown that SPAM1 and other GPI-linked proteins are secreted in the reproductive luminal fluid on membrane vesicles (exosomes or microvesicles) which deliver the proteins to the sperm surface. In investigating the mechanisms underlying exosomal cargo delivery to sperm we have identified two mechanisms for the delivery of GPI-linked proteins which are found in a soluble form as well as the membrane–bound form. Delivery from the soluble form is dependent on lipid carriers secreted in the luminal fluid. Currently, we are working on the mechanism of delivery of transmembrane proteins such as Plasma membrane Ca2+ ATPases (PMCAs) which have been discovered solely on exosomes in the biofluids of both the male and female where they are differentially expressed during estrus.
- 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.
- 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 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.
- Amal Aldossary, M.A.
- Rachel Andrews, B.A.
- Kathie Wu - Undergraduate researcher.
- Rebecca Pollak - Undergraduate researcher.
- Kristine Olli, B.A.
- Lauren Coffua, B.A.
- Pradeepthi Bathala, B.A.
- AL-Dossary A.A., Caplan J., Martin-DeLeon, P.A.: Oviductal Exosome-Sperm Membrane Interaction in Cargo Delivery: Detection of fusion at the nano scale level using 3D super-resolution Structured Illumination Microscopy Journal Biol Chemistry (in revision).
- AL-Dossary A.A., Caplan J., Martin-DeLeon, P.A.: The Contribution of Exosomes/Microvesicles to the Sperm Proteome. Mol. Reprod. Develop in press.
- Modeslski M., Menlah G., Wang Y, Dash S, Wu K, Galileo, DS, Martin-DeLeon, P.A.: Hyaluronidase 2: A Novel Germ Cell Hyaluronidase with Epididymal Expression and Functional Roles in Mammalian Sperm Biol Reprod September 17, doi;10.1095/; Biol Reprod 91(5): 109- 120 (2014).
- Aravindan R.G., Kirn-Safran C.B. Smith, M.A., Martin-DeLeon, P.A.: Ultrastructural changes and Asthenozoopsermia in Murine Spermatozoa lacking the ribosomal protein Hip/Rpl29 gene. Asian J. Androl. Aug 15. Doi;10.4103/1008-682X.133318 (2014).
- Smith MA, Michael, SR., Aravindan RG, Dash S, Shah IS, Dash S, Galileo DS, Martin-DeLeon PA.: Anatase Titanium Dioxide Nanoparticles in Mice: Evidence for Induced Structural and Functional Sperm Defects after Short-, but not Long-, term Exposure. Asian J. Androl. Oct 24 doi: 10.4103/1008-682x.143247 (2014).
- AL-Dossary AA, Strehler, EE, Martin-DeLeon, PA: Expression and Secretion of Plasma Membrane Ca2+-ATPase4a (PMCA4a) during Murine Estrus: Association with Oviductal Exosomes and Uptake in Sperm. Nov 14, PLoS ONE: e80181.doi:10, 1371/jrnl pone.0080181 (2013).
- Patel R, AL-Dossary AA, Stabley DL, Barone, C, Galileo, D, Strehler, EE, Martin-DeLeon, P.A. Plasma membrane Ca2+ -ATPase in Murine Epididymis: Secretion of Splice variants in the luminal Fluid and a Role in Sperm maturation. Biol. Reprod; 89 (6): 1-11 (2013).
- Mei-Jiao Wang, Jia-Xian Ou, Guo-Wu Chen, Jun-Ping Wu, Hui-Juan Shi5 Wai-Sum O, Martin-DeLeon, P. A.: Hong Chen: Does Prohibitin Expression Regulate Mitochondrial Membrane Potential, Sperm Motility, and Male Fertility? Antioxid. Redox Signal. doi: 10.1089/ars.2012.4514. (2012).
- Aravindan, G.R, Fomin,V.R, Naik, U.P., Modelski MJ, Naik MU, Galileo, D. S., Duncan, R.L., Martin-DeLeon, P.A. : CASK interacts with PMCA4b and JAM-A on the mouse sperm flagellum to regulate motility and Ca2+ homeostasis. J Cell Physiol doi: 10. 1002/jcp.24000 (2011).
- Martin-DeLeon, P.A. : Germ-cell hyaluronidases: Their Roles in Sperm Function. International J. Androl.doi 10 1111 1365-2605 (2010).
- Reese KL, Aravindan RG, Griffiths GS, et al. Acidic hyaluronidase activity is present in mouse sperm and is reduced in the absence of SPAM1: evidence for a role for hyaluronidase 3 in mouse and human sperm. Mol reprod Dev. 2010;77(9):759–72.
- Griffiths GS, Galileo DS, Aravindan RG, Martin-DeLeon PA. Clusterin Facilitates Exchange of Glycosyl-Phosphosphatidylinositol-Linkind SPAM1 Between Reproductive Luminal Fluids and Mouse and Human Sperm Membranes. Biology of Reproduction. 2009;81:562–570.
- Griffiths GS, Galileo DS, Reese K, Martin-Deleon PA. Investigating the role of murine epididymosomes and uterosomes in GPI-linked protein transfer to sperm using SPAM1 as a model. Mol Reprod Dev. 2008;75(11):1627–1636.
- 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 Biol 313: 246-255 (2007).
- Martin-DeLeon PA. Epididymal SPAM1 and its impact on sperm function. Mol Cell Endocrinol. 2006;250(1-2):114–121.
- Zhang H, Barnoski BL, Sol-Church K, Stabley DL, Martin-Deleon PA. Murine Spam1 mRNA: involvement of AU-rich elements in the 3'UTR and antisense RNA in its tight post-transcriptional regulation in spermatids. Mol Reprod Dev. 2006;73(2):247–255.
- Martin-DeLeon PA, Zhang H, Evans EA, Jones R, Morales CR, 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: Balazs EA, Hascall VC, eds. Hyaluronan: Structure, Metabolism, Biological Activities, Therapeutic Applications. Vol. I. Edgewater, NJ: Matrix Biology Institute; 2005:229–234.
- Martin-DeLeon PA, Zhang H, Morales CR, et al. Spam1-associated transmission ratio distortion in mice: elucidating the mechanism. Reprod Biol Endocrinol. 2005;3:32.
- Zhang H, Shertok S, Miller K, Taylor L, Martin-Deleon PA. Sperm dysfunction in the Rb(6.16)- and Rb(6.15)-bearing mice revisited: involvement of Hyalp1 and Hyal5. Mol Reprod Dev. 2005;72(3):404–410.
- Morales CR, Badran H, El-Alfy M, Men H, Zhang H, Martin-DeLeon PA. Cytoplasmic localization during testicular biogenesis of the murine mRNA for Spam1 (PH-20), a protein involved in acrosomal exocytosis. Mol Reprod Dev. 2004;69(4):475–482.
- Zhang H, Jones R, Martin-DeLeon PA. Expression and secretion of rat SPAM1(2B1 or PH-20) in the epididymis: role of testicular lumicrine factors. Matrix Biol. 2004;22(8):653–661.
- Zhang H, Morales CR, Badran H, El-Alfy M, Martin-DeLeon PA. Spam1 (PH-20) expression in the extratesticular duct and accessory organs of the mouse: a possible role in sperm fluid reabsorption. Biol Reprod. 2004;71(4):1101–1107.
- Evans EA, Zhang H, Martin-DeLeon PA. SPAM1 (PH-20) protein and mRNA expression in the epididymides of humans and macaques: utilizing laser microdissection/RT-PCR. Reprod Biol Endocrinol. 2003;1:54.
- Zhang H, Martin-Deleon PA. Mouse epididymal Spam1 (pH-20) is released in the luminal fluid with its lipid anchor. J Androl. 2003;24(1):51–58.
- Zhang H, Martin-DeLeon PA. Mouse Spam1 (PH-20) is a multifunctional protein: evidence for its expression in the female reproductive tract. Biol Reprod. 2003;69(2):446–454.
- Martin-DeLeon PA, Piumi F, Canaff L, Rogel-Gaillard C, Hendy GN. 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. 2001;94(1-2):90–91.
- Zhang H, Martin-DeLeon PA. Mouse epididymal Spam1 (PH-20) is released in vivo and in vitro, and Spam1 is differentially regulated in testis and epididymis. Biol Reprod. 2001;65(5):1586–1593.
- Zheng Y, Deng X, Martin-DeLeon PA. Lack of sharing of Spam1 (Ph-20) among mouse spermatids and transmission ratio distortion. Biol Reprod. 2001;64(6):1730–1738.
- Zheng Y, Deng X, Zhao Y, Zhang H, Martin-DeLeon PA. Spam1 (PH-20) mutations and sperm dysfunction in mice with the Rb(6.16) or Rb(6.15) translocation. Mamm Genome. 2001;12(11):822–829.
- Deng X, He Y, Martin-Deleon PA. Mouse Spam1 (PH-20): evidence for its expression in the epididymis and for a new category of spermatogenic-expressed genes. J Androl. 2000;21(6):822–832.
- Zheng Y, Martin-Deleon PA. 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. 1999;54(1):8–16.
- Zheng Y, Martin-Deleon PA. The murine Spam1 gene: RNA expression pattern and lower steady-state levels associated with the Rb(6.16) translocation. Mol Reprod Dev. 1997;46(3):252–257.
- Nagle DL, Martin-DeLeon P, Hough RB, Bucan M. Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5. Proc Natl Acad Sci U S A. 1994;91(15):7237–7241.
- Nigro, J.M., Schweinfest, C.W., Rajkovic, A., Pavlovic, J., Jamal, S., Dottin, R.P., Hart, J.T., Kamarck, M. E., Rae, P.M.M., Carty, M.D. and Martin-DeLeon, P.A. cDNA cloning and mapping of the human creatine kinase M gene to 19q13. Am. J. Hum. Gen. 40:115-125 (1987).
- Taylor, E. F. and Martin-DeLeon, P. A. Familial silver staining patterns of human nucleolus organizer regions, Amer. J. Hum. Gen. 33:67-76 (1981).
- Martin, P.A. Cannabis and Chromosomes. Lancet 1: 370 (1969).
Trustees Distinguished Professor
U.S. Presidential Awardee (PAESMEM)
Faculty Representative to the Board of Trustees
Phone: (302) 831-2249
Fax: (302) 831-2281
Office: 219 McKinly Lab
Lab: 265/267 McKinly Lab
Department of Biological Sciences
University of Delaware
Newark, DE 19716
- B.Sc. (Hons.), M.Sc. - University of the West Indies (Jamaica)
- Ph.D. - University of Western Ontario (Canada)
- Postdoctoral - McGill University (Canada)