Primitive Endoderm Differentiates via a Three-Step Mechanism Involving Nanog and RTK Signaling

SummaryDuring preimplantation mouse development, the inner cell mass (ICM) differentiates into two cell lineages—the epiblast and the primitive endoderm (PrE)—whose precursors are identifiable by reciprocal expression of Nanog and Gata6, respectively. PrE formation depends on Nanog by a non-cell-autonomous mechanism. To decipher early cell- and non-cell-autonomous effects, we performed a mosaic knockdown of Nanog and found that this is sufficient to induce a PrE fate cell autonomously. Strikingly, in Nanog null embryos, Gata6 expression is maintained, showing that initiation of the PrE program is Nanog independent. Treatment of Nanog null embryos with pharmacological inhibitors revealed that RTK dependency of Gata6 expression is initially direct but later indirect via Nanog repression. Moreover, we found that subsequent expression of Sox17 and Gata4—later markers of the PrE—depends on the presence of Fgf4 produced by Nanog-expressing cells. Thus, our results reveal three distinct phases in the PrE differentiation program

[Genetics and molecular pathology of anti-Mullerian hormone and its receptor].

International audienceAnti-müllerian hormone (AMH), a glycoprotein produced by immature Sertoli cells, is responsible in male fetuses for regression of müllerian ducts, the anlagen of Fallopian tubes and uterus in females. AMH binds to a specific type II serine-threonine kinase transmembrane receptor (AMHR-II). A known pathology of AMH and its receptor is the persistent müllerian ducts syndrome (PMDS), a peculiar case of male pseudohermaphroditism, presenting with retention of tubes and uterus in otherwise normally virilized boys, and transmitted with an autosomic recessive mode. Genetic studies on 76 families of patients allowed identification of AMH gene mutations in 45%, and AMHR-II gene mutations in 39% (including a 27 bases deletion in half of the latter). In 15% mutation of none of the two genes was detected, thus mutations are expected in genes coding for other factors of the AMH transduction cascade

Anti-Müllerian hormone receptor defect

International audienceAnti-Müllerian hormone (AMH), produced by gonadal somatic cells, is mainly responsible for the regression of Müllerian ducts--the anlagen of uterus and Fallopian tubes--during male sex differentiation. Like other members of the transforming growth factor beta (TGF-beta) family, AMH signals through two serine/threonine kinase receptors, of which type II is specific, and type I is shared with the bone morphogenetic protein family. Persistent Müllerian duct syndrome is a rare form of male pseudohermaphroditism characterized by the persistence of Müllerian derivatives in otherwise normally virilized males. It is transmitted according to a recessive autosomic pattern and is due, in 84% of cases, to mutations of AMH and AMH receptor type II genes. Serum AMH is normal for age in patients with AMH type II mutations and low or undetectable in those with AMH mutations. In 14% of cases the origin of the condition is unknown

Génétique et pathologie moléculaire de l’hormone anti-müllérienne et de son récepteur

L’hormone anti-müllérienne (AMH) est une glycoprotéine produite par les cellules de Sertoli du testicule immature, responsable chez le fœtus mâle de la régression des canaux de Müller, qui donneront, chez la femme, les trompes de Fallope et l’utérus. Elle agit par liaison à un récepteur membranaire de type II (AMHR-II) à activité sérine-thréonine kinase.Une pathologie connue de l’AMH et de son récepteur est le syndrome de persistance des dérivés müllériens (PMDS) ou syndrome de «l’homme à utérus», un cas particulier de pseudo-hermaphrodisme masculin qui se manifeste, chez des garçons normalement virilisés, par la présence d’un utérus et/ou de trompes. Il s’agit d’un syndrome familial se transmettant habituellement sur un mode autosomique récessif. L’étude de 76 familles de patients provenant de nombreux pays a permis d’identifier dans 45 % des cas des mutations du gène de l’AMH, et dans 39 % des mutations du gène du récepteur AMHR-II (dont une délétion de 27 bases présente dans près de la moitié des cas). Chez 15 % des patients, l’origine génétique n’a pas encore été identifiée, il pourrait s’agir de mutations de facteurs intervenant en aval dans la cascade de transduction de l’AMH

Mutations de l'hormone anti-Müllérienne et de ses récepteurs dans le syndrome de persistance des canaux de Müller (études structure/fonction)

L' hormone anti-Müllérienne (AMH) est un membre de la famille du Transforming Growth Factor-b, impliqué dans la différienciation du tractus génital du foetus mâle. A la surface de la cellule, elle se lie à des récepteurs à activité sérine/théonine kinase de type II (AMHR-II) et de type I:ALK2, ALK3, ALK6 ; puis active des protéines effectrices cytoplasmiques. Des études structure/fonction de mutations naturelles de l'AMH et de l'AMHR-II induisant une persistance de résidus Müllériériens chez les hommes PMDS ont été réalisés.La modélisation tridimensionnelle du domaine C-terminal de l'AMH a permis de comprendre l'effet de mutations faux-sens sur sa sécrétion. Les récepteurs tronqués en amont de leur domaine transmenbrannaire sont instables, les autres sont déficients en activité kinase.Centre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Persistent müllerian duct syndrome with crossed testicular ectopia.

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Persistence of Müllerian derivatives in males.

International audienceThe 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

DNA methyl transferases are differentially expressed in the human anterior eye segment

International audienceDNA methylation is an epigenetic mark involved in the control of genes expression. Abnormal epigenetic events have been reported in human pathologies but weakly documented in eye diseases. The purpose of this study was to establish DNMT mRNA and protein expression levels in the anterior eye segment tissues and their related (primary or immortalized) cell cultures as a first step towards future in vivo and in vitro methylomic studies

AMH and AMH receptor defects in persistent Müllerian duct syndrome.

International audienceAnti-Müllerian hormone (AMH) produced by fetal Sertoli cells is responsible for regression of Müllerian ducts, the anlage for uterus and Fallopian tubes, during male sex differentiation. A member of the transforming growth factor-beta superfamily, AMH signals through two transmembrane receptors, type II which is specific and type I receptors, shared with the bone morphogenetic protein family. Mutations of the AMH and AMH receptor type II (AMHR-II) genes lead to persistence of the uterus and Fallopian tubes in males. Both conditions are transmitted according to a recessive autosomal pattern and are symptomatic only in males. Affected individuals are otherwise normally virilized, undergo normal male puberty; and may be fertile if testes, tightly attached to the Fallopian tubes, can be replaced in the scrotum. Approximately 85% of the cases are due, in similar proportions, to mutations of the AMH or AMHR-II gene. The genetic background does not influence the phenotype, the only difference is the level of circulating AMH which is normal for age in AMHR-II mutants and usually low or undetectable in AMH gene defects. This is due to lack of secretion, explained by the localization of the mutations in critical regions, based on the assumed 3D structure of the molecule. Similarly, lack of translocation to the surface membrane is responsible for the inactivity of AMHR-II molecules bearing mutations in the extracellular domain. In 15% of cases, the cause of the persistent Mullerian duct syndrome is unknown and could be related to complex malformations of the urogenital region, unrelated to AMH physiology