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J Y Picard

Publications and source records attributed to J Y Picard.

At least 19 recordsLinked to original sources
PubMed2001

Ovarian granulosa cell tumors express a functional membrane receptor for anti-Müllerian hormone in transgenic mice.

Anti-Müllerian hormone inhibits granulosa cell growth and function. Both anti-Müllerian hormone and its type II receptor are expressed in normal granulosa cells. We show by histologic and molecular analyses that ovarian tumors developing in transgenic mice, obtained by targeted oncogenesis using an anti-Müllerian hormone promoter-SV40 oncogene construct, are of granulosa-cell origin. Because tissue-specific, cell-surface molecules are of particular interest for the analysis and treatment of tumors, we examined the expression of anti-Müllerian hormone type II receptor in the ovaries of these transgenic mice. We demonstrate that the anti-Müllerian hormone type II receptor is expressed not only in normal ovarian follicles, but also in granulosa cell tumors. Using a cell line derived from one of these tumors, we show that the anti-Müllerian hormone type II receptor protein is present on the surface of tumor cells and binds anti-Müllerian hormone. Furthermore, we show that the anti-Müllerian hormone receptor is functional in the granulosa tumor cell line, with anti-Müllerian hormone treatment inducing selective activation of Smad1. In conclusion, in this study we present a new murine transgenic model of granulosa cell tumors of the ovary and, using this model, we demonstrate for the first time cell-surface expression of a highly tissue-specific molecule, anti-Müllerian hormone type II receptor, as well as the selective activation of Smad proteins by anti-Müllerian hormone, in granulosa tumor cells.

Animals↗
PubMed2001

Autosomal recessive segregation of a truncating mutation of anti-Müllerian type II receptor in a family affected by the persistent Müllerian duct syndrome contrasts with its dominant negative activity in vitro.

Anti-Müllerian hormone belongs to the TGFbeta family whose members exert their effects by signaling through two related serine/threonine kinase receptors. Mutations of the anti-Müllerian hormone type II receptor occur naturally, causing the persistent Müllerian duct syndrome. In a family with two members with persistent Müllerian duct syndrome and one normal sibling, we detected two novel mutations of the anti-Müllerian hormone type II receptor gene. One, transmitted by the mother to her three sons, is a deletion of a single base leading to a stop codon, causing receptor truncation after the transmembrane domain. The other, a missense mutation in the substrate-binding site of the kinase domain, is transmitted by the father to the two sons affected by persistent Müllerian duct syndrome, indicating a recessive autosomal transmission as in other cases of persistent Müllerian duct syndrome. Truncating mutations in receptors of the TGFbeta family exert dominant negative activity, which was seen only when each of the mutant anti-Müllerian hormone receptors was overexpressed in an anti-Müllerian hormone-responsive cell line. We conclude that assessment of dominant activity in vitro, which usually involves overexpression of mutant genes, does not necessarily produce information applicable to clinical conditions, in which mutant and endogenous genes are expressed on a one to one basis.

Animals↗
PubMed2000

Detection of minimal levels of serum anti-Müllerian hormone during follow-up of patients with ovarian granulosa cell tumor by means of a highly sensitive enzyme-linked immunosorbent assay.

Granulosa cell tumors (GCT) are ovarian neoplasms that tend to recur and spread in the pelvis and the abdomen several years after the initial treatment. Anti-Mülerian hormone (AMH) is a reliable serum marker of these tumors. To enhance the availability and the sensitivity of serum AMH determination, we developed an ultrasensitive enzyme-linked immunosorbent assay. In this work we compare the results of serum AMH levels, obtained using the ultrasensitive and the traditional assays, in 31 patients with ovarian GCT followed up for up to 7 yr. The ultrasensitive enzyme-linked immunosorbent assay has a significantly higher sensitivity than the traditional one. This resulted in the detection of low serum AMH levels, which were undetectable with the traditional assay, in several cases including one patient in whom a recurrence of a GCT had developed and two patients in whom the treatment had not been completely successful. These cases highlight the importance of the availability of a highly sensitive assay allowing evaluation with high precision of the results of treatment and to detect the recurrences of GCT at an early, preclinical stage.

Adolescent↗
PubMed2000

Molecular mechanisms of hormone-mediated Müllerian duct regression: involvement of beta-catenin.

Regression of the Müllerian duct in the male embryo is one unequivocal effect of anti-Müllerian hormone, a glycoprotein secreted by the Sertoli cells of the testis. This hormone induces ductal epithelial regression through a paracrine mechanism originating in periductal mesenchyme. To probe the mechanisms of action of anti-Müllerian hormone, we have studied the sequence of cellular and molecular events involved in duct regression. Studies were performed in male rat embryos and in transgenic mice overexpressing or lacking anti-Müllerian hormone, both in vivo and in vitro. Anti-Müllerian hormone causes regression of the cranial part of the Müllerian duct whereas it continues to grow caudally. Our work shows that this pattern of regression is correlated with a cranial to caudal gradient of anti-Müllerian hormone receptor protein, followed by a wave of apoptosis spreading along the Müllerian duct as its progresses caudally. Apoptosis is also induced by AMH in female Müllerian duct in vitro. Furthermore, apoptotic indexes are increased in Müllerian epithelium of transgenic mice of both sexes overexpressing the human anti-Müllerian hormone gene, exhibiting a positive correlation with serum hormone concentration. Inversely, apoptosis is reduced in male anti-Müllerian hormone-deficient mice. We also show that apoptosis is a decisive but not sufficient process, and that epitheliomesenchymal transformation is an important event of Müllerian regression. The most striking result of this study is that anti-Müllerian hormone action in peri-Müllerian mesenchyme leads in vivo and in vitro to an accumulation of cytoplasmic beta-catenin. The co-localization of beta-catenin with lymphoid enhancer factor 1 in the nucleus of peri-Müllerian mesenchymal cells, demonstrated in primary culture, suggests that overexpressed beta-catenin in association with lymphoid enhancer factor 1 may alter transcription of target genes and may lead to changes in mesenchymal gene expression and cell fate during Müllerian duct regression. To our knowledge, this is the first report that beta-catenin, known for its role in Wnt signaling, may mediate anti-Müllerian hormone action.

Animals↗
PubMed1999

Persistence of Müllerian derivatives in males.

The persistent müllerian duct syndrome is a rare, autosomal recessive disorder, characterized by the persistence of müllerian duct derivatives-uterus and fallopian tubes-in genetic males otherwise normally virilized. We have collected DNA from 69 families with this syndrome. In 45%, a mutation of the anti-müllerian hormone (AMH) gene was detected; 52% were homozygous. The level of circulating AMH was extremely low in the great majority of patients, even before puberty, when AMH levels are normally high. Single-strand conformation polymorphism (SSCP)-polymerase chain reaction (PCR) was a very effective screening method. In 39% of families, characterized by an AMH level normal for the age of the patient, a mutation of the type II receptor of AMH was detected by automatic sequencing, because SSCP-PCR was not very effective. Forty-eight percent of the mutations were homozygous. A 27-base-pair deletion in exon 10 was noted in 45% of the families. When this very common mutation is not taken into account, the proportion of recurrent mutations is 42% for the AMH gene and 33% for the AMH receptor type II gene. In 16% of families, no mutation of either the AMH or the AMH receptor gene was detectable; this group may correspond to mutations of unknown genes involved in AMH processing or in downstream AMH transduction.

Anti-Mullerian Hormone↗
PubMed1998

Early expression of AMH in chicken embryonic gonads precedes testicular SOX9 expression.

In mammals, anti-Müllerian hormone (AMH) is produced by Sertoli cells from the onset of testicular differentiation and by granulosa cells only after birth. SOX9, a transcription factor related to the testis-determining factor SRY, is expressed in mouse testis 1 day before AMH. To determine the relationship between AMH and SOX9 in birds, we cloned the AMH promoter in search of SOX9 response elements, and we compared the expression of AMH and SOX9 in the gonads of chick embryos using in situ hybridization. Potential SOX response elements were found in the AMH promoter; however, AMH is expressed in both sexes at stage 25, 1 day before the first SOX9 transcripts appear in the male gonads. SOX9 is never expressed in the female. These results do not support the hypothesis that SOX9 could trigger the expression of testicular AMH in the chick but does not exclude a later role in testis development.

Animals↗
PubMed1998

Embryology and endocrinology of genital development.

In the human male fetus, testes develop by the 7th week and begin to secrete two hormones: anti-müllerian hormone (AMH) induces the regression of müllerian ducts, the anlagen of the uterus, fallopian tubes and upper vagina, upon binding to a specific membrane receptor, whereas testosterone induces the differentiation of the wolffian ducts into the epididymes, vasa deferentia and seminal vesicles. In some target tissues, testosterone is converted to dihydrotestosterone, which is responsible for masculinization of the urogenital sinus and external genitalia. Both androgens act upon binding to the same nuclear receptor. In the absence of AMH and androgen action, or example in the female or in abnormal male differentiation, the internal and external genital primordia differentiate following the female pathway, even in the absence of ovaries. In males, an impaired function of the AMH-dependent pathway results in the persistent müllerian duct syndrome, a disorder characterized by the presence of uterus and fallopian tubes in otherwise normally virilized boys. Several mutations found in the AMH and AMH-receptor genes explain the pathophysiology of this syndrome.

Anti-Mullerian Hormone↗
PubMed1997

A mouse Sertoli cell line expressing anti-Müllerian hormone and its type II receptor.

Anti-Müllerian hormone (AMH) induces the regression of Müllerian ducts in the male foetus; it is secreted by prepubertal testicular Sertoli cells and repressed at puberty. Using an AMH promoter/Simian virus 40 (SV40) oncogene fusion gene, we generated transgenic mouse lines exhibiting heritable Sertoli cell tumorigenesis. One cell line, derived from an adult male, expressed mRNAs characteristic of mature Sertoli cells, but no AMH. Two other cell lines were obtained from pretumoral testes at 6.5 days. One was cloned to yield SMAT1, whose expression pattern was characteristic of prepubertal Sertoli cells, namely no transferrin and high SF-I and AMH expression. SMAT1 also secretes AMH protein into the culture medium and expresses the AMH receptor. To the best of our knowledge, this is the first Sertoli cell line stably expressing AMH and its receptor. Our results show that, in targeted oncogenesis, the timing of cell line derivation plays a critical role even when using a developmentally regulated promoter.

Animals↗
PubMed1996

Mutant isoforms of the anti-Müllerian hormone type II receptor are not expressed at the cell membrane.

Anti-Müllerian hormone, a member of the transforming growth factor beta superfamily, produces early regression of Müllerian ducts in the male fetus through binding to a serine/threonine kinase receptor, homologous to type II receptors of the transforming growth factor beta (TGF-beta) family. A splice mutation of this receptor, described in a patient with abnormal retention of Müllerian derivatives, generates two mutant isoforms, one lacking the second exon and the other bearing an insertion of 12 bases between exons 2 and 3. Using hemagglutinin-tagged recombinant receptors, we have visualized wild type and mutant receptors in COS cells by Western blotting and immunoprecipitation. The 82-kDa, endoglycosidase H-insensitive, mature form of the wild type receptor is reduced to 68 kDa by N-glycosidase F treatment. Mutant receptor isoforms, 73 and 63 kDa for the long and short form, respectively, are sensitive to endoglycosidase H, suggesting that they are retained in the endoplasmic reticulum. Indeed, only the wild type receptor was expressed on the cell surface and bound iodinated anti-Müllerian hormone. These results provide a biological explanation for the failure of the mutant receptor to induce Müllerian regression.

Alternative Splicing↗
PubMed1996

Cloning and expression of the chick anti-Müllerian hormone gene.

Müllerian duct regression in male embryos is due to early production by fetal Sertoli cells of anti-Müllerian hormone, a homodimeric protein of the transforming growth factor- beta superfamily. In mammals, both female Müllerian ducts develop into the uterus and Fallopian tubes, whereas in birds, the right oviduct does not develop. To gain insight into sex differentiation in birds, we have cloned the cDNA for chick anti-Müllerian hormone using antibodies raised against the partially purified protein. Expression cloning was required because of the lack of cross-hybridization between mammalian and chick anti-Müllerian hormone DNA. The chick DNA and protein are significantly longer, due to insertions that abolish nucleotide homology, except in the cDNA coding for the C-terminal, bioactive part of the protein. Nevertheless, the general structure of the gene, sequenced from the transcription initiation to the polyadenylation site, and the main features of the protein are conserved between the chick and mammals. The chick anti-Müllerian hormone gene is expressed at high levels in Sertoli cells of the embryonic testes and in lower amounts in both ovaries, higher levels being reached on the left side after 10 days of incubation.

Amino Acid Sequence↗
PubMed1996

A 27 base-pair deletion of the anti-müllerian type II receptor gene is the most common cause of the persistent müllerian duct syndrome.

The persistent müllerian duct syndrome, characterized by the lack of regression of müllerian derivatives, uterus and tubes in otherwise normally masculinized males, is a genetically transmitted disorder implicating either anti-müllerian hormone (AMH), a member of the transforming growth factor-beta superfamily, or its type II receptor, a serine/threonine kinase homologous to the receptors of other members of the transforming growth factor-beta superfamily. We have now performed molecular studies in a total of 38 families. The basis of the condition, namely 16 AMH and 16 AMH receptor mutations, was identified in 32 families. The type of genetic defect could be predicted from the level of serum AMH which is very low or undetectable in patients with AMH mutations and at the upper limit of normal in receptor mutations. Whereas AMH mutations are extremely diverse, patients from 10 out of 16 families with receptor mutations had a 27 bp deletion in exon 10 on at least one allele. This deletion is thus implicated in approximately 25% of patients with persistent müllerian duct syndrome. All AMH and AMH receptor mutations were consistent with an autosomal recessive mode of transmission.

Amino Acid Sequence↗
PubMed1996

[Molecular biology of the persistent Müllerian duct syndrome].

The persistent Müllerian duct syndrome, characterized by the presence of uterus and tubes in otherwise normally masculinized 46,XY males, is a familial autosomal recessive disorder due to defects of synthesis or action of anti-Müllerian hormone. We have performed molecular studies in a total of 38 families and we have identified the basis of the condition, namely 16 anti-Müllerian hormone and 16 anti-Müllerian hormone receptor mutations, in 32 families.

Anti-Mullerian Hormone↗
PubMed1995

Testicular degeneration in three patients with the persistent müllerian duct syndrome.

UNLABELLED: The persistent müllerian duct syndrome, characterized by the presence of uterus and tubes in males, is a familial disorder due to defects of synthesis or action of anti-müllerian hormone, a Sertoli cell glycoprotein responsible for the regression of müllerian derivatives in normal male fetuses. Patients are normally virilized and testicular production of testosterone is normal. Both testes may be cryptorchid; alternatively, one may be descended into the inguinal canal or scrotum, together with the müllerian derivatives, a condition known as "hernia uteri inguinalis". We have recently observed three patients affected by the persistent müllerian duct syndrome who experienced progressive degeneration of testicular tissue. In two, functional testicular tissue was still present some months after birth, but deteriorated progressively later. In one patient, testicular tissue was already absent at birth, but the normal virilization of external genitalia indicated that testicular degeneration must have occurred late during fetal life, after the expected time of regression of male müllerian ducts. CONCLUSION: The high incidence of degeneration of testicular tissue in the persistent müllerian duct syndrome could be indirectly linked to anatomical abnormalities which could favour testicular torsion, known to induce testicular regression.

Chronic Disease↗
PubMed1995

Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor.

Anti-Müllerian hormone (AMH) and its receptor are involved in the regression of Müllerian ducts in male fetuses. We have now cloned and mapped the human AMH receptor gene and provide genetic proof that it is required for AMH signalling, by identifying a mutation in the AMH receptor in a patient with persistent Müllerian duct syndrome. The mutation destroys the invariant dinucleotide at the 5' end of the second intron, generating two abnormal mRNAs, one missing the second exon, required for ligand binding, and the other incorporating the first 12 bases of the second intron. The similar phenotypes observed in AMH-deficient and AMH receptor-deficient individuals indicate that the AMH signalling machinery is remarkably simple, consisting of one ligand and one type II receptor.

Alternative Splicing↗
PubMed1994

Molecular genetics of the persistent müllerian duct syndrome: a study of 19 families.

A rare form of familial male pseudohermaphroditism, the persistent Müllerian duct syndrome (PMDS) is characterized by persistence of uterus and Fallopian tubes in 46,XY phenotypic males and is ascribed to defects in the synthesis or action of anti-Müllerian hormone (AMH). Biologically, PMDS is heterogeneous: in some cases, bioactive AMH is normally expressed by testicular tissue while, in others, no AMH is produced, suggesting the possibility of an AMH gene mutation, several of which have already been described. Molecular analysis of the AMH gene has now been performed in 21 additional patients and their families. In 6 patients, with normal serum concentration of AMH, the AMH gene was normal or contained only polymorphisms and silent mutations, supporting the hypothesis that the condition is due to end-organ resistance. Nine novel mutations were discovered in the remaining subjects, with low or undetectable levels of serum AMH. These mutations, when present in homozygotes or compound heterozygotes, were associated with the PMDS phenotype, the same mutation never being observed in two different families. The three first exons of the AMH gene appear particularly mutation-prone, although they are less GC rich than the 2 last ones and code for the N-terminal part of the AMH protein, which is not in itself essential to bioactivity.

Anti-Mullerian Hormone↗
PubMed1994

Cloning, expression, and alternative splicing of the receptor for anti-Müllerian hormone.

Anti-Müllerian hormone, also called Müllerian-inhibiting substance or factor, is a glycoprotein dimer belonging to the transforming growth factor-beta superfamily and synthesized by immature Sertoli cells and postnatal granulosa cells. Anti-Müllerian hormone plays a key role in sex differentiation by inducing the regression of Müllerian ducts in the male fetus. It is also responsible for the stunting and masculinization of fetal ovaries in bovine freemartin fetuses and may be involved in the control of follicular maturation in the postnatal ovary. Using a degenerate probe for a consensus region of the transforming growth factor-beta receptor superfamily to screen a complementary DNA library from rabbit fetal ovaries, we cloned a complementary DNA coding for a transmembrane serine/threonine kinase, which is expressed around the fetal Müllerian duct, in fetal and adult granulosa cells, and in immature Sertoli cells. Two transcripts, generated by alternative splicing of an exon coding for an N-terminal 61-amino acid domain, are strongly expressed in anti-Müllerian hormone target organs and Sertoli cells. The longer, 569-amino acid, isoform binds anti-Müllerian hormone when transiently expressed in COS cells and is believed to encode its functional receptor.

Amino Acid Sequence↗
PubMed1993

The persistent müllerian duct syndrome: a rare cause of cryptorchidism.

The persistent Müllerian duct syndrome is characterized by the retention of Müllerian derivatives in patients otherwise normally virilized. Clinically, the persistence of uterus and tubes leads either to cryptorchidism or inguinal hernia, depending on whether or not the Müllerian derivatives can be mobilized during testicular descent. The condition is usually discovered at surgery, however preoperative sonography could allow the diagnosis to be made preoperatively. The molecular basis of the persistent Müllerian duct syndrome is heterogeneous, and is reflected by wide variations in the serum concentration of anti-Müllerian hormone. Some cases are apparently due to end-organ resistance, and are associated with normal serum levels of the hormone. Others, characterized by absent or low hormone concentrations, can be explained by mutations of the gene coding for anti-Müllerian hormone, which are distributed along the whole length of the coding region.

Adolescent↗