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R.-Marc Pelletier, Ph.D.

Professor

R-808 Département de pathologie et biologie cellulaire

Pavillon Roger-Gaudry

Faculté de médecine

Université de Montreal

2900 bvd Édouard Montpetit, Montréal, QC

H3T 1J4 

Email address: This email address is being protected from spambots. You need JavaScript enabled to view it.

Tel.: (514) 343-5765

 

Field of research :

The production of spermatozoa relies on the fine regulation of inter-related strategic mechanisms. Errors in any of these individual mechanisms may lead to male infertility in addition to pathologies of the testis that will require treatment.

Our research is focussed on the regulation of three distinct strategic mechanisms specifically:

  1. The role of junction proteins in the induction, the maintenance and the regulation of meiosis
  2. The significance of cholesterol mechanism in the maintenance of spermatogenesis and male fertility
  3. The development and maintenance of immunotolerance in the normal testis and its deregulation during the inflammation of the testis and spontaneous autoimmune orchitis (AIO).

1) The role of junction proteins in meiotic competence

The three major types of intercellular contacts or junctions in the testis are, the tight junctions (or occlusive junctions), the gap junctions and the adhering junctions. Each of these types of contacts regulates particular strategic aspects of the testicular function and of the spermatogenic process. For instance, the occlusive junctions when assembled into occluding zonules constitute the anatatomical basis of the blood-testis barrier which prevents circulating blood from entering freely into the parenchyma of the testis. The gap junctions allow communications at one time amongst adjacent supporting somatic Sertoli cells at other time amongst these and the contacting germinal cells. The adhering junctions are established before the gap junctions and are believe to have an impact on their behaviour and on testicular growth. We study the regulation of the formation and the dismantling of each type of junctions together with its impact on the normal spermatogenesis and the effects of its deregulation during diverse pathologies of the testis.

2) The significance of cholesterol mechanism in the maintenance of spermatogenesis and male fertility

Cholesterol is vital to all cells. However, too much cholesterol is lethal. Therefore, the amounts of the compound in tissues, in occurrence here in the testis, must be precisely and continuously regulated to allow cell survival and prevent cell death. Cholesterol amounts are regulated at one time by specialized enzymes at other times through selective transporters of cholesterol. We study the action of both, the enzymes and the transporters. We study the action of enzymes implicated in the hydrolysis and/or the esterification of cholesterol specifically, hormone-sensitive lipase (HSL), HMGCoA reductase (HMG Co Ared) and the two isozymes Acylcoenzyme A:cholesterol O-acyltransferase (ACAT-1) and (ACAT-2). In addition, when the production of cholesterol exceeds the requirements in cholesterol of cells then, the compound must be imported. In this perspective, we study the selective cholesterol transporters specifically, SR-BI, SR-BII, CD36 et ABCA1. Interestingly, these molecules act as multiligands sharing several vital cellular functions in addition to simply cholesterol transport. Therefore, when the function of these transporters is challenged following lipid pathologies there is much more than only the transport of cholesterol that is affected and the function of the whole testicular function is modified. In fact, several studies have shown that the experimental ablation of one or more genes involved in the cholesterol metabolism will bear most significant repercussions on the male fertility as well as on the female fertility and even on the fœto-maternal relation that result in the death of the embryo.

3)    The development and maintenance of immunotolerance in the normal testis and its deregulation during the inflamation of the testis and spontaneous autoimmune orchitis (AIO).

Around the turn of the last century, it was found that spermatozoa are highly antigenic and that an individual was not allergic to its own spermatozoa but only for as long as the original location of the gametes was maintained. If they were injected into another location of the body then, they would cause a severe autoimmune aggression resulting in testis failure. In fact autoimmune orchitis (an inflamation of the testis) which often leads to infertility has been shown to occur spontaneously in some rodents, in mink, dog as well as in human. Infertility increases with age and it may result from dysfunctions in either the testis, the ovary, the uterus or even foeto-maternal relations. For our part, our attention is focussed on the factors that contribute to the establishment and maintenance of immunotolerance in the normal testis and on the errors in this mechanism that lead to its deregulation causing testis failure and pathologies and infertility. Amongst the factors that we are studying are the presence and the impact of auto-antibodies on apoptosis and phagocytosis, the action of cytokines specifically, Fas, IL-1, IL-6, TNF alpha, interferon and of the CD4 (the Th17 in particular) and CD8 cells and macrophages in the development of spontaneous auto-immune orchitis in the hope of building the foundation for its treatment. Amongst the approaches we currently use are enriche tissue fractionation, Western blotting, lipids quantification, molecular biology, immunolabeling, confocal microscopy etc and the use of mice whose genetic background has been experimentally modified. In addition, we also use the mink (Mustela vison) as an animal model because of its many points of similarities with humans.

 

Laboratory members:

Name

Position

Email address

Christopher Garcia

Étudiant à la maîtrise
(en co-direction; directrice: Maria Leiza Vitale)

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Casimir D. Akpovi

Stagiaire post-doctoral

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Neloum Djimadoum

Étudiant à la maîtrise
(co-directrice: Maria Leiza Vitale)

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List of publications:

Lustig, L., Denduchis, B., Ponzio, R., Lauzon, M. and Pelletier, R.-M. 2000 Passive immunization with anti-laminin IgG modifies the integrity of the seminiferous epithelium and induces arrest of spermatogenesis in the Guinea pig. Biol. Reprod. 62:1505-1514.

Pelletier, R.-M., Yoon, S. Y.‡, Kabbaj, O.‡ and Vitale, M. L. 2000 Development and maintenance of fertility in the male mink. Scientifur 24: 16-24.

Wong, J., Luckers, L., Okawara, Y.*, Pelletier, R.-M. and Taketo, T. 2000 Follicular development and atresia in the B6.YTIR sex-reversed mouse ovary. Biol. Reprod. 63: 756-762.

Vitale, M.L., Cardin, J.,Gilula, N. B., Carbajal, M. E.* and Pelletier, R.-M. 2001 Dynamics of connexin 43 levels and distribution in the mink (Mustela vison) anterior pituitary are associated with seasonal changes in anterior pituitary prolactin content. Biol. Reprod. 64: 625-633.

Kabbaj, O.‡, Holm, C., Vitale, M. L., and Pelletier, R.-M. 2001 Expression, activity and subcellular localization of the testicular hormone-sensitive lipase (HSL) during post natal development in Guinea pig. Biol. Reprod. 65: 601-612

Kabbaj, O.‡, Yoon, S. R.‡, Holm, C., Rose, J. Vitale, M. L., and Pelletier, R.-M. 2003 Relationship of the hormone sensitive lipase (HSL)-mediated modulation of cholesterol metabolism in individual compartments of the testis to serum pituitary hormone and testosterone concentrations in a seasonal breeder, the mink (Mustela vison). Biol. Reprod. 68: 722-734.

Zheng GF*, Pelletier R-M, Solinet, S ‡ and Vitale ML. 2005 Serum-dependent actin cytoskeleton remodelling in the anterior pituitary folliculostellate cell line TtT/GF: Participation of the actin-binding protein cortactin.J. Molecular Histology 2005; 36:461-474. (J. Molecular Histology DOI: 10.1007/s10735-006-9021-1)

Fortin M-E*, Pelletier R-M, Meilleur MA*, Vitale ML 2006 Modulation of GJA1 turnover and intercellular communication by pro-inflammatory cytokines in the anterior pituitary folliculo-stellate cell ligne TtT/GF. Biol. Reprod.74: 2-12.

Gyamera-Acheampong C, Tanttibhedyangul W, Weerachatyanukul H, Tadros H, Xu J-W. van de Loo, Pelletier R-M, Tanphaichitr N, Mbikay M. 2006 Sperm from mice genetic Deficiency for the Proteinase PC4 exhibit accelerated capacitation, precocious acrosome reaction, reduced binding to egg zona pellucida and impaired fertility ability. Biol Reprod, 74: 666-673.

Akpovi CD‡, Yoon, SR ‡, Vitale ML, and Pelletier R.-M. 2006 Predominance of one of the SR-BI isoforms is associated with increased esterified cholesterol levels not apoptosis in mink testis. J. Lipid Research, 47:2233-2247.

Meilleur M-A*, Akpovi CD, Pelletier R-M, Vitale ML 2007 TNF-α-induced anterior pituitary folliculostellate TtT/GF cell uncoupling is mediated by Cx43 dephosphorylation
Endocrinology; 148:5913-5924.

Pelletier R-M, Yoon SR‡, Akpovi CD‡, Silvas E*, Vitale ML. Defects in the regulatory clearance mechanisms favor the breakdown of self-tolerance during spontaneous autoimmune orchitis. Am JPhysiol Regul Integr Comp Physiol 296: R743–R762, 2009. First published December 3, 2008; doi:10.1152/ajpregu.90751.2008.

Akpovi, C.D. and Pelletier, R.M. 2009 A manual method for the isolation of seminiferous tubule-enriched fractions that preserves the phosphorylated and glycosylated forms of proteins. Chapter 9, pp 159-167. Lafond, J., and Vaillancourt, C., Ed., Human Embryogenesis : Methods and Protocols, Humana Press, Totowa, NJ.

Chen Li, Lafond Julie and Pelletier R.-M. 2009 A novel technical approach for the measurement of individual ACAT-1 and ACAT-2 enzymatic activity in the seminiferous tubules of the testis. Chapter 10, pp 168-177. Lafond, J., and Vaillancourt, C., Ed., Human Embryogenesis : Methods and Protocols, Humana Press, Totowa, NJ.

Pelletier R-M, Yoon SR‡, Akpovi CD‡, Silvas E*, Vitale ML 2009 Defects in the regulatory clearance mechanisms favor the breakdown of self-tolerance during spontaneous autoimmune orchitis. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology; 296:R743-R762.

Vitale ML, Akpovi CD‡, Pelletier R.-M 2009 Cortactin/Tyrosine-Phosphorylated cortactin interaction with with connexin 43 in mouse seminiferous tubules. Microscopy Research and Technique 72: 856-867.

Hermo, L., Pelletier, R.-M, D. G. Cyr and C. E. Smith 2010 Surfing the Wave, Cycle, Life History, and Genes/Proteins Expressed by Testicular Germ Cells. Part 1: Background to Spermatogenesis, Spermatogonia, and Spermatocytes. Microcopy Research and Technique 73: 243-278.

Hermo, L., Pelletier, R.-M, D. G. Cyr and C. E. Smith 2010 Surfing the Wave, Cycle, Life History, and Genes/Proteins Expressed by Testicular Germ Cells. Part 2: Changes in Spermatid Organelles Associated With Development of Spermatozoa. Microcopy Research and Technique 73: 279-319.

Hermo, L., Pelletier, R.-M, D. G. Cyr and C. E. Smith 2010 Surfing the Wave, Cycle, Life History, and Genes/Proteins Expressed by Testicular Germ Cells. Part 3: Developmental Changes in Spermatid Flagellum and Cytoplasmic Droplet and Interaction of Sperm With the Zona Pellucida and Egg Plasma Membrane. Microcopy Research and Technique 73: 320-363.

Hermo, L., Pelletier, R.-M, D. G. Cyr and C. E. Smith 2010 Surfing the Wave, Cycle, Life History, and Genes/Proteins Expressed by Testicular Germ Cells. Part 4: Intercellular Bridges, Mitochondria, Nuclear Envelope, Apoptosis, Ubiquitination, Membrane/Voltage-Gated Channels, Methylation/Acetylation, and Transcription Factors. Microcopy Research and Technique 73: 364-408.

Hermo, L., Pelletier, R.-M, D. G. Cyr and C. E. Smith 2010 Surfing the Wave, Cycle, Life History, and Genes/Proteins Expressed by Testicular Germ Cells. Part 5: IntercellularJunctions and Contacts Between Germs Cells and Sertoli Cells and Their Regulatory Interactions, Testicular Cholesterol, and Genes/Proteins Associated With More Than One Germ Cell Generation. Microcopy Research and Technique 73: 408-494.

Jiménez, L. M., Binelli M. , Bertolin, K., Pelletier R-M, and Murphy, B. 2010 Scavenger Receptor B-1 and luteal function in the mouse. J. Lipid Research 51: 2362-2371. Published ahead of print April 2010, doi:1194.

Pelletier, R.-M., Akpovi‡, C. D., Day. R. and Vitale, ML 2011 Cx43 expression, phosphorylation and distribution in the normal and autoimmune orchitic testis with a look at gap junctions joining germ cell-to-germ cells. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology.300: R121-R139; published ahead of print October 20, 2010 doi:10.1152/ajpregu.00500.2010.

Pelletier, R.-M. 2012 The blood-testis barrier: The permeability, the proteins and the lipids. Progress in Histochemistry and Cytochemistry 46:49-127.