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This text analyses the first two decades of the École normale supérieure d’institutrices situated in Fontenay-aux-Roses since its foundation in 1880. Created to train elite female primary teaching staff (headmistresses and teachers in teacher training colleges, female inspectors of primary schools, etc.), the school of Fontenay was deeply influenced by its director of studies: Félix Pécaut (1828-1898). A supporter of an ambitious programme of instruction for women and an advocate of a model of laïcité (secularity) derived from his own belonging to the protestant religion, Félix Pécaut encouraged the “fontenaysiennes” to develop their critical thinking and apply it to every subject. This research analyses the youth of the Fontenay school through the mark that Pécaut made on a dozen of his students. This research is based on texts written by several of his former pupils who spoke up at the turn of the century when attacks against the school were proliferating in the context of the “War between the two Frances” (“Guerre des deux France”). Pécaut being a Dreyfus supporter, he converted Ferdinand Buisson to his cause and led his former pupils to keep a vigilant eye on the situation of the country in this context of political and social crisis. During this chaotic period, the school of Fontenay was frequently attacked in the press. Several “fontenaysiennes” stayed faithful to the legacy of Pécaut in their own teacher training colleges during the Belle Époque. They applied a liberal discipline based on self-government, replicating the traditional morning conferences and keeping in mind Pécaut’s aphorism addressed to “his daughters”: “Dare to be!”.‪, Cet article revient sur les deux premières décennies d’existence de l’École normale supérieure d’institutrices de Fontenay-aux-Roses à partir de sa fondation en 1880. Créée pour former l’élite du corps enseignant primaire féminin (les directrices et professeures d’écoles normales, d’écoles primaires supérieures et les inspectrices), l’école de Fontenay est marquée pendant cette période par l’aura de son directeur des études : Félix Pécaut (1828-1898). Défenseur d’une instruction ambitieuse pour les filles et partisan d’une conception de la laïcité scolaire maintenant une aspiration à la transcendance, cet ancien pasteur protestant encourage les fontenaysiennes à développer leur esprit critique et le principe du libre examen en tout domaine. C’est à travers l’empreinte que Pécaut a laissée sur une dizaine de fontenaysiennes que cet article aborde la jeunesse de l’école de Fontenay. Cette recherche repose sur les textes produits par plusieurs anciennes élèves de « Monsieur l’Inspecteur », qui s’expriment, pour beaucoup d’entre elles, au tournant du XIXᵉ et du XXᵉ siècle, alors que les attaques se multiplient contre Fontenay dans le contexte de la « Guerre des deux France ». L’engagement dreyfusard de Félix Pécaut, qui entraîne avec lui Ferdinand Buisson et qui appelle la communauté des fontenaysiennes à la vigilance, attire en effet sur l’école de Fontenay les foudres de l’opinion conservatrice. La fin du siècle est l’occasion de batailles de plumes dans la presse autour de l’École normale supérieure d’institutrices. De nombreuses fontenaysiennes font malgré tout fructifier l’héritage de Pécaut dans leurs écoles normales pendant toute la Belle Époque, appliquant une discipline libérale fondée sur le self-government, reprenant la tradition des conférences du matin et gardant en tête la maxime pécaldienne adressée à « ses filles » : « Osez être ! ».

International audience; Maturity-onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron-2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β-cell volume. These defects were associated with a 30% decrease in expression of the pro-endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Background & Aims The exocrine pancreas consists of acinar cells that produce digestive enzymes transported to the intestine through a branched ductal epithelium. Chronic pancreatitis is characterized by progressive inflammation, fibrosis, and loss of acinar tissue. These changes of the exocrine tissue are risk factors for pancreatic cancer. The cause of chronic pancreatitis cannot be identified in one quarter of patients. Here, we investigated how duct dysfunction could contribute to pancreatitis development. Methods The transcription factor Hnf1b, first expressed in pancreatic progenitors, is strictly restricted to ductal cells from late embryogenesis. We previously showed that Hnf1b is crucial for pancreas morphogenesis but its postnatal role still remains unelucidated. To investigate the role of pancreatic ducts in exocrine homeostasis, we inactivated the Hnf1b gene in vivo in mouse ductal cells. Results We uncovered that postnatal Hnf1b inactivation in pancreatic ducts leads to chronic pancreatitis in adults. Hnf1bΔduct mutants show dilatation of ducts, loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis. We deciphered the early events involved, with down-regulation of cystic disease–associated genes, loss of primary cilia, up-regulation of signaling pathways, especially the Yap pathway, which is involved in acinar-to-ductal metaplasia. Remarkably, Hnf1bΔduct mutants developed pancreatic intraepithelial neoplasia and promote pancreatic intraepithelial neoplasia progression in concert with KRAS. We further showed that adult Hnf1b inactivation in pancreatic ducts is associated with impaired regeneration after injury, with persistent metaplasia and initiation of neoplasia. Conclusions Loss of Hnf1b in ductal cells leads to chronic pancreatitis and neoplasia. This study shows that Hnf1b deficiency may contribute to diseases of the exocrine pancreas and gains further insight into the etiology of pancreatitis and tumorigenesis., Graphical abstract

Meconnue de l’historiographie, Jeanne Desparmet-Ruello est une intellectuelle qui, dans le sillage de Jaures, considere l’ecole laique comme une priorite pour la Troisieme Republique. Dreyfusarde, elle est la fondatrice et presidente de l’Universite populaire lyonnaise qu’elle fait vivre entre 1899 et 1905. Femme de science aux convictions rationalistes, elle milite pour appliquer partout la laicite scolaire dans un contexte de concurrence avec l’ecole catholique. Libre penseuse, elle se prete a des manifestations qui lui attirent des attaques dans la presse lyonnaise et des conflits avec son administration. Directrice du lycee de jeunes filles de Lyon, Jeanne Desparmet-Ruello eprouve les limites de sa liberte d’action et de parole, dans un contexte ou les femmes professeurs, pour faire se faire accepter socialement, doivent se conformer a un ideal de discretion. Par ailleurs, les engagements de Jeanne Desparmet-Ruello ne sont pas toujours juges compatibles avec son statut de fonctionnaire, qui impose devoir de reserve et de neutralite. C’est donc sous un pseudonyme qu’on la retrouve dans les colonnes de la Fronde, quotidien qui associe la lutte feministe au combat pour les droits de l’homme dans le contexte de l’Affaire. Grande actrice de l’education populaire, Jeanne Desparmet-Ruello se revendique socialiste, mais adopte des positions plutot heterodoxes. En quoi consiste donc son socialisme ? Peut-il etre qualifie de jauresien ? Pourquoi est-il indissociable de son engagement feministe, dreyfusard et libre penseur ?

Cet article d'introduction constitue une reflexion sur la notion de « couple d'intellectuels ». Il propose tout d'abord un bilan historiographique autour de ce concept en commentant les rares travaux dedies jusqu'ici a des couples d'intellectuels dans l'histoire contemporaine francaise. Il s'interroge ensuite sur les raisons qui expliquent ces lacunes scientifiques, en montrant que la notion de « couples d'intellectuels » se situe au carrefour d'historiographies qui ont jusqu'alors peu communique : l'histoire des femmes et du genre, l'histoire intellectuelle et politique, l'histoire de la vie privee et des emotions. Ce texte se donne aussi pour but de caracteriser la periode etudiee (annees 1880 – annees 1940) en montrant qu'elle connait un double mouvement de rupture en ce qui concerne les couples d'intellectuels : c'est a la fois le moment de naissance et d'institutionnalisation du mariage d'amour et du modele du « couple d'egaux » promu par les feministes ; c'est aussi une epoque ou emerge l'intellectuelle au feminin comme figure sociale. D'abord connues sous le syntagme de « femmes nouvelles » a la Belle Epoque, les femmes etudiees ici ont progressivement acquis un acces aux etudes secondaires et superieures et, plus globalement, au monde intellectuel et elles ont decide de s'engager dans la vie sociale et politique de leur pays. Elles sont devenues ce qu'on ose aujourd'hui qualifier d'intellectuelles au feminin. Quel role leur conjoint – voire leur conjointe dans le cas du couple de lesbiennes Cahun / Moore – a-t-il joue dans leur parcours ? En quoi l'analyse des vies privees de ces couples permet-elle de saisir la facon dont se construit une production intellectuelle et un engagement politique et social ?

En partie fonde sur l'analyse de la riche correspondance que Louise et Georges Renard ont entretenue au cours de leur liaison adultere, cet article s'emploie a etudier les liens entre leur experience amoureuse et leur conception du couple. Ce travail interroge aussi la facon dont Louise Renard, meconnue de l'historiographie, acquiert, au contact de son second mari, une veritable stature intellectuelle. Libres penseurs, socialistes, feministes, Louise et Georges Renard partagent un combat en faveur de la reforme du mariage, qu'ils considerent comme indispensable a toute reforme sociale. Ce texte s'attache a demeler les fils de l'elaboration d'une production intellectuelle et d'un engagement communs.

Marie Fuster, nee Baertschi, epouse Edouard Fuster le 23 aout 1900. Recue premiere a l’agregation de lettres en 1899, professeure et oratrice charismatique, elle appartient a la vague de femmes lettrees formees par la Troisieme Republique dans les nouvelles institutions nees des lois scolaires des annees 1880. Republicains engages preoccupes par la question sociale, Marie et Edouard forment en fait un veritable couple d’intellectuels dans lequel le partage de valeurs communes n’empeche pas la poursuite d’une trajectoire autonome. L’etude des engagements de Marie permet de lire, en filigrane, les combats et les paradoxes d’un couple engage au tournant du xixe et du xxe siecle.

International audience; The transcription factors HNF1B and Pax2, co-expressed in the Wolffian duct and ureteric bud epithelia, play essential roles during the early steps of mouse kidney development. In humans, heterozygous mutations in these genes display a number of common kidney phenotypes, including hypoplasia and multicystic hypoplastic kidneys. Moreover, a high prevalence of mutations either in HNF1B or PAX2 has been observed in children with renal hypodysplasia. To gain a better understanding of Hnf1b and Pax2 interactions in vivo, we generated compound heterozygous mice for Hnf1b and Pax2 null alleles. We show here that compound heterozygous mutants display phenotypes similar to severe congenital anomalies of the kidney and the urinary tract (CAKUT), including strong hypoplasia of the kidneys, caudal ectopic aborted ureter buds, duplex kidneys, megaureters and hydronephrosis. At a molecular level, compound mutants show a delay in nephron segment and medullar interstitial differentiation, increased apoptosis and a transient decrease in Lim1 and Wnt4 expression. We also observe a perturbation of smooth muscle differentiation around the ureter associated with a local down-regulation in transcript levels of Bmp4 and Tbx18, two key regulators involved in ureter smooth muscle formation, thus explaining, at least in part, megaureters. These results together uncover a novel role of Hnf1b as a modifier of the Pax2 haplo-insufficient phenotype and show that these two transcription factors operate in common pathways governing both kidney morphogenesis and ureter differentiation. This mouse model should provide new insights into the pathogenic mechanisms of human CAKUT, the most frequent developmental defect identified in newborns.

Mouse metanephric kidney development begins with the induction of the ureteric bud (UB) from the caudal portion of the Wolffian duct by metanephric mesenchymal signals. While the UB undergoes branching morphogenesis to generate the entire urinary collecting system and the ureter, factors secreted by the UB tips induce surrounding mesenchymal cells to convert into epithelia and form the nephrons, the functional units of the kidney. Epithelial branching morphogenesis and nephrogenesis are therefore tightly orchestrated; defects in either of these processes lead to severe kidney phenotypes ranging from hypoplasia to complete aplasia. However, the underlying regulatory networks have been only partially elucidated. Here, we identify the transcription factor vHNF1 (HNF1β) as a crucial regulator of these early developmental events. Initially involved in timing outgrowth of the UB and subsequent branching, vHNF1 is also required for nephric duct epithelial maintenance, Müllerian duct formation and early nephrogenesis. Mosaic analyses further suggest a cell-autonomous requirement for vHNF1 in the acquisition of a specialized tip domain and branching morphogenesis. vHNF1 exerts these intricate functions at least in part through the direct control of key regulatory molecules involved in different aspects of early kidney development. Notably, vHNF1 acting directly upstream of Wnt9b appears to orchestrate Wnt signaling action in the mesenchymal-epithelial transitions underlying the initiation of nephrogenesis. These results demonstrate that vHNF1 is an essential transcriptional regulator that, in addition to the known later functions in normal duct morphogenesis, plays a crucial role during the earliest stages of urogenital development and provide novel insights into the regulatory circuits controlling events.

Heterozygous mutations in the HNF1beta/vHNF1/TCF2 gene cause maturity-onset diabetes of the young (MODY5), associated with severe renal disease and abnormal genital tract. Here, we characterize two fetuses, a 27-week male and a 31.5-week female, carrying novel mutations in exons 2 and 7 of HNF1beta, respectively. Although these mutations were predicted to have different functional consequences, both fetuses displayed highly similar phenotypes. They presented one of the most severe phenotypes described in HNF1beta carriers: bilateral enlarged polycystic kidneys, severe pancreas hypoplasia and abnormal genital tract. Consistent with this, we detected high levels of HNF1beta transcripts in 8-week human embryos in the mesonephros and metanephric kidney and in the epithelium of pancreas. Renal histology and immunohistochemistry analyses of mutant fetuses revealed cysts derived from all nephron segments with multilayered epithelia and dysplastic regions, accompanied by a marked increase in the expression of beta-catenin and E-cadherin. A significant proportion of cysts still expressed the cystic renal disease proteins, polycystin-1, polycystin-2, fibrocystin and uromodulin, implying that cyst formation may result from a deregulation of cell-cell adhesion and/or the Wnt/beta-catenin signaling pathway. Both fetuses exhibited a severe pancreatic hypoplasia with underdeveloped and disorganized acini, together with an absence of ventral pancreatic-derived tissue. beta-catenin and E-cadherin were strongly downregulated in the exocrine and endocrine compartments, and the islets lacked the transporter essential for glucose-sensing GLUT2, indicating a beta-cell maturation defect. This study provides evidence of differential gene-dosage requirements for HNF1beta in normal human kidney and pancreas differentiation and increases our understanding of the etiology of MODY5 disorder.

International audience; Vezatin, a protein associated to adherens junctions in epithelial cells, is already expressed in mouse oocytes and during pre-implantation development. Using a floxed strategy to generate a vezatin-null allele, we show that the lack of zygotic vezatin is embryonic lethal, indicating that vezatin is an essential gene. Homozygous null embryos are able to elicit a decidual response but as early as day 6.0 post-coitum mutant implantation sites are devoid of embryonic structures. Mutant blastocysts are morphologically normal, but only half of them are able to hatch upon in vitro culture and the blastocyst outgrowths formed after 3.5 days in culture exhibit severe abnormalities, in particular disrupted intercellular adhesion and clear signs of cellular degeneration. Notably, the junctional proteins E-cadherin and beta-catenin are delocalized and not observed at the plasma membrane anymore. These in vitro observations reinforce the idea that homozygous vezatin-null mutants die at the time of implantation because of a defect in intercellular adhesion. Together these results indicate that the absence of zygotic vezatin is deleterious for the implantation process, most likely because cadherin-dependent intercellular adhesion is impaired in late blastocysts when the maternal vezatin is lost.