Jacques J. Tremblay

Laval University | ULAVAL · Department of Obstetrics, Gynecology and Reproduction

Leydig cells produce hormones required for the development and maintenance of sex characteristics and fertility in males. MEF2 transcription factors are important regulators of Leydig cell gene expression and steroidogenesis. ERK5 is an atypical member of the MAP kinase family that modulates transcription factor activity either by direct phosphoryl...

Leydig cells, located in the testis interstitial space, are the primary source of testosterone in males. Testosterone plays critical roles in both reproductive and metabolic functions and therefore is essential for male health. Steroidogenesis must be properly regulated since dysregulated hormone production can lead to infertility and metabolic dis...

The peptide hormone insulin-like 3 (INSL3) is produced almost exclusively by Leydig cells of the male gonad. INSL3 has several functions such as fetal testis descent and bone metabolism in adults. Insl3 gene expression in Leydig cells is not hormonally regulated but rather is constitutively expressed. The regulatory region of the Insl3 gene has bee...

Hormone-induced Leydig cell steroidogenesis requires rapid changes in gene expression in response to various hormones, cytokines, and growth factors. These proteins act by binding to their receptors on the surface of Leydig cells leading to activation of multiple intracellular signaling cascades, downstream of which are several kinases, including p...

Leydig cells produce testosterone, a hormone essential for male sex differentiation and spermatogenesis. The pituitary hormone, LH, stimulates testosterone production in Leydig cells by increasing the intracellular cAMP levels, which leads to the activation of various kinases and transcription factors, ultimately stimulating the expression of the g...

In the testis, Leydig cells produce steroid hormones that are needed to masculinize typical genetic males during fetal development and to initiate and maintain spermatogenesis at puberty and adulthood, respectively. Steroidogenesis is initiated by the transfer of cholesterol from the outer to the inner mitochondrial membrane through the action of s...

Background: Leydig cells produce testosterone and insulin-like 3, two hormones essential for male sex differentiation and reproductive function. The orphan nuclear receptor COUP-TFII and the zinc finger factor GATA4 are two transcription factors involved in Leydig cell differentiation, gene expression and function. Objectives: Several Leydig cel...

Leydig cells produce androgens which are essential for male sex differentiation and reproductive functions. Steroidogenesis, as well as expression of several genes in Leydig cells, are stimulated by LH/cAMP and repressed by AMP/AMPK. One of those genes is Plau, which codes for the urokinase-type plasminogen activator (uPA), a secreted serine protea...

In brief: The insulin-like 3 (INSL3) hormone produced by Leydig cells is essential for proper male sex differentiation, but the regulation of Insl3 expression remains poorly understood. This study describes a new physical and functional cooperation between the nuclear receptors SF1 and COUP-TFII in Insl3 expression. Abstract: INSL3, a hormone ab...

Defining how genes get turned on and off in a correct spatiotemporal manner is integral to our understanding of the development, differentiation, and function of different cell types in both health and disease. Testis development and subsequent male sex differentiation of the XY fetus are well-orchestrated processes that require an intricate networ...

Cell differentiation and acquisition of specialized functions are inherent steps in events that lead to normal tissue development and function. These processes require accurate temporal, tissue, and cell-specific activation or repression of gene transcription. This is achieved by complex interactions between transcription factors that form a unique...

Within Leydig cells, steroidogenesis is induced by the pituitary luteinizing hormone (LH). The binding of LH to its receptor increases cAMP production, which then activates the expression of genes involved in testosterone biosynthesis. One of these genes codes for the steroidogenic acute regulatory (STAR) protein. STAR is part of a complex that shu...

La protéine STAR est essentielle à la synthèse de testostérone par les cellules de Leydig. L’expression du gène Star implique la participation de nombreuses hormones, dont l’hormone de croissance (GH). Bien que l’implication de la GH dans la stimulation de la stéroïdogenèse et de l’expression de Star dans les cellules de Leydig soit connue depuis p...

Members of the pre-B-cell leukemia transcription factor (PBX) family of homeoproteins are mainly known for their involvement in hematopoietic cell differentiation and in the development of leukemia. The four PBX proteins, PBX1, PBX2, PBX3 and PBX4, belong to the three amino acid loop extension (TALE) superfamily of homeoproteins which are important...

Leydig cells produce androgens that are essential for male sex differentiation and reproductive function. Leydig cell function is regulated by several hormones and signaling molecules, including growth hormone (GH). Although GH is known to upregulate Star gene expression in Leydig cells, its molecular mechanism of action remains unknown. The STAT5B...

Steroid production in Leydig cells is stimulated mainly by the pituitary luteinizing hormone, which leads to increased expression of genes involved in steroidogenesis, including the gene encoding the steroidogenic acute regulatory (STAR) protein. Mono(2-ethylhexyl)phthalate (MEHP), the active metabolite of the widely used plasticizer DEHP, is known...

In males, Leydig cells are the main producers of testosterone and insulin-like 3 (INSL3), two hormones essential for sex differentiation and reproductive functions. Chicken ovalbumin upstream promoter-transcription factors I (COUP-TFI/NR2F1) and COUP-TFII (NR2F2) belong to the steroid/thyroid hormone nuclear receptor superfamily of transcription fa...

The nuclear receptor COUP-TFII/NR2F2 is expressed in adult Leydig cells and conditional deletion of the Coup-tfii/Nr2f2 gene impedes their differentiation. Steroid production is also reduced in COUP-TFII-depleted Leydig cells supporting an additional role in steroidogenesis for this transcription factor. COUP-TFII action in Leydig cells remains to...

Background GATA4 is a transcription factor essential for male sex determination, testicular differentiation during fetal development, and male fertility in the adult. GATA4 exerts part of its function by regulating multiple genes in the steroidogenic enzyme pathway. In spite of these crucial roles, how the activity of this factor is regulated remai...

The three FOXA transcription factors are mainly known for their roles in the liver. However, Foxa3-deficient mice become progressively sub/infertile due to germ cell. Since no data was available regarding the localization of the FOXA3 protein in the testis, immunohistochemistry was performed on mouse testis sections. In the fetal testis, a weak but...

Insulin-like 3 (INSL3), a Leydig cell-specific hormone, is essential for testis descent during fetal life and bone metabolism in adults. Despite its essential roles in male reproductive and bone health, very little is known regarding its transcriptional regulation in Leydig cells. To date, few transcription factors have been shown to activate INSL3...

Leydig cells are essential for male reproductive development and health throughout life. Production of androgens [testosterone, dihydrotestosterone (DHT)] as well as intermediate steroids [progesterone, dihydroprogesterone (DHP)] is tightly regulated. In the mouse, the 3α-hydroxysteroid dehydrogenase enzyme (3α-HSD, AKR1C14) catalyses the interconv...

The nuclear receptor NR4A1 is expressed in steroidogenic Leydig cells where it plays pivotal roles by regulating the expression of several genes involved in steroidogenesis and male sex differentiation including Star, HSD3B2, and Insl3. Activation of the cAMP and Ca2+ signalling pathways in response to LH stimulation leads to a rapid and robust act...

Testosterone is essential for spermatogenesis and the development of male sexual characteristics. However, steroidogenesis produces a significant amount of reactive oxygen species (ROS), which can disrupt testosterone production. The myocyte enhancer factor 2 (MEF2) is an important regulator of organogenesis and cell differentiation in various tiss...

Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. Consequently, the process of steroid hormone biosynthesis is finely regulated. In the testis, the main steroidogenic cells are the Leydig cells. There are two distinct populations of Leydig cells that arise during d...

Significance On activation, blood platelets package components from their cytoplasm into microparticles (MPs), tiny vesicles released by cytoplasmic membrane budding and shedding. Given that MPs can impact other cellular lineages on internalization, we aimed to decipher the mechanisms promoting MP internalization by cellular recipients. We modeled...

Testosterone production by Leydig cells is a tightly regulated process requiring synchronized expression of several steroidogenic genes by numerous transcription factors. Myocyte enhancer factor 2 (MEF2) are transcription factors recently identified in somatic cells of the male gonad. In other tissues, MEF2 factors are essential regulators of organ...

In Leydig cells, STAR participates in cholesterol shuttling from the outer to the inner mitochondrial membrane, the rate-limiting step in steroidogenesis. Steroid hormone biosynthesis and steroidogenic gene expression are regulated by LH, which activates various signaling pathways and transcription factors, including cAMP/Ca(2+)/CAMK-MEF2. The four...

Steroid hormones regulate essential physiological processes, and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by luteinizing hormone (LH) via its receptor leading to increased cyclic AMP (cAMP) production and expression of the steroidogenic acut...

GATA4 is a transcription factor required for testicular differentiation and for male fertility. In spite of its crucial roles in male reproduction, how the activity of this factor is regulated has yet to be fully understood. The GATA4 protein is phosphorylated on at least two serine residues. This includes GATA4 S105, which has been reported to mod...

Steroid hormones regulate essential physiological processes, and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by luteinizing hormone (LH) via its receptor leading to increased cyclic AMP (cAMP) production and expression of the steroidogenic acut...

Testosterone production is dependent on cholesterol transport within mitochondrial matrix, an essential step mediated by a protein complex containing the steroidogenic acute regulatory (STAR) protein. In steroidogenic Leydig cells, Star expression is hormonally regulated and involves several transcription factors. NR2F2 (COUP-TFII) is an orphan nuc...

INSL3, a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance little is known about the molecular mechanisms controlling Insl3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for COUP-TFII, an orphan nuclear receptor known to play...

Leydig cell steroidogenesis is mainly regulated by LH via increased cAMP production leading to STAR protein activation. STAR is essential for cholesterol shuttling inside mitochondria where steroidogenesis is initiated. Accumulating evidence suggest that persistent organochlorine compounds disrupt testicular function but the mechanism of action rem...

Leydig cell steroidogenesis is controlled by the pituitary gonadotropin LH that activates several signaling pathways, including the Ca(2+)/calmodulin kinase I (CAMKI) pathway. In other tissues, CAMKI regulates the activity of the MEF2 transcription factors. MEF2 are essential regulators of cell differentiation and organogenesis in numerous tissues...

In the gonads and adrenal glands, the transient increase in steroidogenesis after hormonal stimulation requires modulation of steroidogenic acute regulatory protein (Star) expression and activity in a tightly regulated process involving cAMP and Ca(2+). In Leydig cells, the cAMP and Ca(2+) pathways account for most if not all of LH-induced steroido...

In the gonads and adrenal glands, the transient increase in steroidogenesis after hormonal stimulation requires modulation of steroidogenic acute regulatory protein (Star) expression and activity in a tightly regulated process involving cAMP and Ca(2+). In Leydig cells, the cAMP and Ca(2+) pathways account for most if not all of LH-induced steroido...

Steroid hormones are required for several physiological processes and inadequate steroid hormone levels are associated with various pathological conditions. Thus, steroid hormone synthesis must be tightly regulated. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by LH that acts through a G protein-coupled receptor le...

Leydig cells produce two hormones, testosterone and insulin-like 3 (INSL3), that are essential for proper male sex differentiation as well as for the initiation and maintenance of spermatogenesis. Leydig cell differentiation requires platelet-derived growth factor receptor a (PDGFRA), located on Leydig cells, and its ligand PDGF-A synthesized by Se...

Elevated levels of organochlorines, including pesticides and industrial compounds, some of which are known endocrine disruptors, have been reported in human and wildlife populations worldwide. To test the hypothesis that prenatal exposure to organochlorines contaminating the Far North adversely affects reproductive development and function, we deve...

Platelet-derived growth factor (PDGF) A is secreted by Sertoli cells and acts on Leydig precursor cells, which express the receptor PDGFRA, triggering their differentiation into steroidogenically active Leydig cells. There is, however, no information regarding the molecular mechanisms that govern Pdgfra expression in Leydig cells. In this study, we...

Steroid hormone biosynthesis requires the steroidogenic acute regulatory protein (STAR). STAR is part of a protein complex that transports cholesterol through the mitochondrial membrane where steroidogenesis begins. Several transcription factors participate to direct the proper spatiotemporal and hormonal regulation of the Star gene in Leydig cells...

The Ladybird-like homeobox gene 2 (Lbx2) belongs to the homeodomain-containing family of transcription factor that are known to play crucial role in various developmental processes. During early mouse embryogenesis, Lbx2 was shown to be expressed in the developing eye, brain and urogenital system. Although Lbx2 was detected in the testis and epidid...

Several signals, such as hormones and signaling molecules, have been identified as important regulators of Leydig cell differentiation and function. Conveying these signals and translating them into a genomic response to ensure an accurate physiological output requires the action of a network of transcription factors, including those belonging to t...

Insulin-like peptide 3 (INSL3) is a hormone produced by fetal and adult Leydig cells of the mammalian testis. During embryonic life INSL3 is required for testicular descent, whereas in adults it is involved in bone metabolism and male germ cell survival. Despite these important roles, the molecular mechanisms regulating INSL3 expression remain poor...

There are increasing evidence in the literature reporting the detrimental effects of endocrine disruptors on the development and function of the male reproductive system. One example is cryptorchidism, or undescended testis, caused by exposure to excessive estrogens. Estrogens, acting through the estrogen receptor alpha (ERalpha), have been shown t...

The steroidogenic acute regulatory protein plays an essential role in steroid biosynthesis in steroidogenic cells. It is involved in the transport of cholesterol through the mitochondrial membrane where the first step of steroidogenesis occurs. Star gene expression in testicular Leydig cells is regulated by the pituitary LH through the cAMP signali...

Expression of steroidogenic enzyme-encoding genes in testicular Leydig cells is complex and involves several transcription factors including the orphan nuclear receptor NUR77 (NR4A1) and the bZIP factor CCAAT/enhancer binding protein beta (EBPbeta). How these transcription factors are integrated into a functional network, however, remains to be ful...

Excessive exposure to estradiol represents the main risk factor for endometrial cancer. The abnormally high estradiol levels in the endometrium of women with endometrial cancer are most likely due to overproduction by the tumour itself. Endometrial cancer cells express the genes encoding the steroidogenic enzymes involved in estradiol synthesis. He...

The Nur77 (Nr4a1) gene, encoding the orphan nuclear receptor NUR77 (NR4A1), is an immediate early response gene whose expression is rapidly induced by a variety of physiologic stimuli. Nur77 is expressed in several organs, including the classic steroidogenic tissues: gonads and adrenal. In MA-10 Leydig cells, NUR77 has been shown to regulate expres...

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that plays an essential role in oxygen homeostasis. HIF-1alpha is constitutively made in cells; however, it is ubiquitinated and degraded under normoxic conditions. Hypoxia prevents the ubiquitination of HIF-1alpha, resulting in stabilization of the protein and activation of tar...

Cholesterol transport in the mitochondrial membrane, an essential step of steroid biosynthesis, is mediated by a protein complex containing the steroidogenic acute regulatory (StAR) protein. The importance of this transporter is underscored by mutations in the human StAR gene that cause lipoid congenital adrenal hyperplasia, male pseudohermaphrodit...

It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain t...

Insulin-like 3 (INSL3) is a small peptide produced by testicular Leydig cells throughout embryonic and postnatal life and by theca and luteal cells of the adult ovary. During fetal life, INSL3 regulates testicular descent in males, whereas in adults, it acts as an antiapoptotic factor for germ cells in males and as a follicle selection and survival...

Bile ductular proliferation is markedly upregulated in biliary fibrosis and cirrhosis. However, the mechanisms regulating this upregulation in bile ductular proliferation have not been defined. Recently, we demonstrated that expression of the ectonucleotidase nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/Entpd2) by portal fibroblasts (PF)...

Strategy used to derive the degenerate PCR used to identify additional homeoproteins expressed in the male reproductive system. (A) Schematic representation of a homeoprotein with the homeodomain (HD) represented by a black box. DNA sequence alignment of the HD of 16 homeoproteins that have in common a lysine at position 50 of the homeodomain. Sequ...

Expression of Lbx2 in Leydig cell lines by Northern blot. Total RNA from MA-10, mLTC-1, TM3 and R2C Leydig cell lines was extracted using the RNeasy Plus extraction kit (Qiagen, Mississauga, Ontario, Canada) and analyzed by Northern blot. Twenty μg of RNA were separated by agarose-formaldehyde gel electrophoresis and then transferred onto a nylon m...

Homeoproteins are a class of transcription factors that are well-known regulators of organogenesis and cell differentiation in numerous tissues, including the male reproductive system. Indeed, a handful of homeoproteins have so far been identified in the testis and epididymis where a few were shown to play important developmental roles. Through a d...

Homeoproteins are a large family of transcription factors known to play critical roles in several biological processes such as organogenesis, embryogenesis and cell differentiation. Homeobox genes are expressed in several tissues throughout development and the reproductive organs are no exception. So far, previous studies have demonstrated the impl...

Leydig cells present in the testicular interstitium are the main site of testosterone production in males. During fetal and neonatal life, a specific population of Leydig cells (fetal Leydig cells, FLC) is responsible for androgen production and masculinization of the male foetus. During postnatal life, the FLC population regresses and is substitut...

The Kruppel-like factors (KLF) are a family of transcription factors that comprises 16 members in mammals. Most tissues have been reported to express one or several KLFs and the testis is no exception. Indeed, KLF4, 5, 6 and 13 have all been detected in the adult testis by Northern blot. No data is available regarding expression of these factors at...

Transcription factors are at the center stage of several cellular processes, in which they play essential roles as receivers, interpreters, and conveyers of numerous extracellular signals. These signals are the cues to which cells must respond and transcription factors are indispensable to translate these signals into a genomic response. Depending...

Insulin-like 3 (INSL3) is a hormone produced by fetal and adult Leydig cells of the testis and by theca and luteal cells of the adult ovary. In males, INSL3 regulates testicular descent during fetal life, whereas in adults, it acts as a germ cell survival factor. In the ovary, INSL3 regulates oocyte maturation. Despite its importance for male sex d...

Insulin-like 3 (INSL3) is a hormone produced by testicular Leydig cells throughout life. During embryonic life it regulates an essential step of testicular descent, whereas in adults it acts as a male germ cell survival factor. Despite the importance of INSL3 for male sex differentiation and function, very little is known regarding the molecular me...

The human HSD3B2 gene encodes the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 2 (3beta-HSD2) enzyme that is required for steroid hormone biosynthesis. Mutations in the hHSD3B2 gene are responsible for a form of congenital adrenal hyperplasia and male pseudohermaphroditism whereas overexpression of hHSD3B2 has been recently assoc...

The human (h) 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase type 2 (3beta-HSD2) enzyme, encoded by the hHSD3B2 gene, is mainly found in gonads and adrenals. This enzyme catalyzes an essential early step in the biosynthesis of all classes of steroid hormones. The critical nature of the enzyme is supported by the occurrence of human synd...

In mammals, sex development is a genetically and hormonally controlled process that begins with the establishment of chromosomal or genetic sex (XY or XX) at conception. At approximately 6 to 7 weeks of human gestation or embryonic day e11.5 in the mouse, expression of the Y chromosome-linked sex determining gene called SRY (described in detail in...

Understanding how genes get turned on or off is central to the study of biological processes in both health and disease. Several regulatory mechanisms, which can be positive or negative, have been implicated in the control of tissue-and cell-specific gene expression. These include modulation of chromatin structure, DNA methylation, and the regulati...

Steroidogenic factor 1 (SF-1) is a transcription factor belonging to the nuclear receptor superfamily. SF-1 regulates the expression of many genes involved in reproduction, steroidogenesis, and sexual differentiation. An important SF-1 target for male sexual differentiation is the gene encoding the Müllerian-inhibiting substance hormone that induce...

During early mouse embryogenesis, Pitx1 (pituitary homeobox 1), a member of the bicoid subgroup of PAIRED homeobox-containing transcription factors, marks the stomodeum, oral ectoderm, pituitary and first branchial arch in the anterior part of the embryo and lateral plate mesoderm only in the posterior half of the embryo. We have now defined PITX1...

Steroidogenesis is a tightly regulated process that is dependent on pituitary hormones. In steroidogenic tissues, hormonal stimulation triggers activation of an intracellular signalling pathway that typically involves cAMP production, activation of PKA, and phosphorylation of target transcription factors. In the classic cAMP signalling pathway, pho...

Gonadal gene expression is regulated by pituitary hormones acting through the cAMP/protein kinase A (PKA) signal transduction pathway. The downstream molecular effectors of these signals, however, have yet to be fully understood. We have recently shown that cAMP stimulation of gonadal cells leads to phosphorylation of the transcription factor GATA-...