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1. The Antidepressant Action of Fluoxetine Involves the Inhibition of Dlx5/6 in Cortical GABAergic Neurons through a TrkB-Dependent Pathway

Author

Rym Aouci, Anastasia Fontaine, Amïn Vion, Lou Belz, Giovanni Levi, and Nicolas Narboux-Nême

Subjects
fluoxetine, Dlx5/6, TrkB-CREB, Parvalbumine, depression, Cytology, QH573-671
Abstract

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients’ response to antidepressant treatment.

Published
2024
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2. Dlx5/6 Expression Levels in Mouse GABAergic Neurons Regulate Adult Parvalbumin Neuronal Density and Anxiety/Compulsive Behaviours

Author

Rym Aouci, Mey El Soudany, Zakaria Maakoul, Anastasia Fontaine, Hiroki Kurihara, Giovanni Levi, and Nicolas Narboux-Nême

Subjects
GABAergic neurons, DLX5/6 genes, parvalbumin, behaviour, gene regulation, autism, Cytology, QH573-671
Abstract

Neuronal circuits integrating Parvalbumin-positive GABAergic inhibitory interneurons (PV) are essential for normal brain function and are often altered in psychiatric conditions. During development, Dlx5 and Dlx6 (Dlx5/6) genes are involved in the differentiation of PV-interneurons. In the adult, Dlx5/6 continue to be expressed at low levels in most telencephalic GABAergic neurons, but their importance in determining the number and distribution of adult PV-interneurons is unknown. Previously, we have shown that targeted deletion of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in altered behavioural and metabolic profiles. Here we evaluate the consequences of targeted Dlx5/6 gene dosage alterations in adult GABAergic neurons. We compare the effects on normal brain of homozygous and heterozygous (Dlx5/6VgatCre and Dlx5/6VgatCre/+ mice) Dlx5/6 deletions to those of Dlx5 targeted overexpression (GABAergicDlx5/+ mice). We find a linear correlation between Dlx5/6 allelic dosage and the density of PV-positive neurons in the adult prelimbic cortex and in the hippocampus. In parallel, we observe that Dlx5/6 expression levels in GABAergic neurons are also linearly associated with the intensity of anxiety and compulsivity-like behaviours. Our findings reinforce the notion that regulation of Dlx5/6 expression is involved in individual cognitive variability and, possibly, in the genesis of certain neuropsychiatric conditions.

Published
2022
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3. Dlx5 and Dlx6 expression in GABAergic neurons controls behavior, metabolism, healthy aging and lifespan

Author

François Tronche, Thomas Bourgeron, Gladys Alfama, Sébastien Parnaudeau, Serge Luquet, Cécile Vernochet, Giovanni Levi, Anastasia Fontaine, Nicolas Narboux-Nême, Rim Hassouna, Camille de Lombares, Fabrice de Chaumont, Elodie Ey, Eglantine Heude, Christophe Olivo-Marin, Heude, Eglantine, Nouvelles cibles pour l'ostéoporose: des cellules souches mésenchymateuses à la régulation de l'ostéogénèse et de la masse osseuse - - TARGETBONE2017 - ANR-17-CE14-0024 - AAPG2017 - VALID, Association métabolisme/cognition : nouvelles voies de régulation impliquant les neurones GABAergiques - - METACOGNITION2017 - ANR-17-CE37-0007 - AAPG2017 - VALID, Health and the Understanding of Metabolism, Aging and Nutrition - HUMAN - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602757 - VALID, Physiologie moléculaire et adaptation (PhyMA), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This research was partially supported by the EU Consortium HUMAN (EU-FP7-HEALTH-602757) to G.L. and by the ANR grants TARGETBONE (ANR-17-CE14-0024) to GL and METACOGNITION (ANR-17-CE37-0007) to GL, S.L., F.T and an ATM grant to NN-N, CdL is supported by a grant of the French Ministry of Research., ANR-17-CE14-0024,TARGETBONE,Nouvelles cibles pour l'ostéoporose: des cellules souches mésenchymateuses à la régulation de l'ostéogénèse et de la masse osseuse(2017), ANR-17-CE37-0007,METACOGNITION,Association métabolisme/cognition : nouvelles voies de régulation impliquant les neurones GABAergiques(2017), European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Physiologie Moléculaire et Adaptation (PhyMA), Muséum National d'Histoire Naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Analyse d'images biologiques - BioImage Analysis (AIQ), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This research was partially supported by the EU Consortium HUMAN (EU-FP7-HEALTH-602757) to G.L. and by the ANR grants TARGETBONE (ANR-17-CE14-0024) to GL and METACOGNITION (ANR-17-CE37-0007) to GL, S.L., F.T and 'Cognitio', an ATM grant to NN-N, CdL is supported by a grant of the French Ministry of Research., ANR-17-CE14-0024,TARGETBONE,Nouvelles cibles pour l’ostéoporose: des cellules souches mésenchymateuses à la régulation de l'ostéogénèse et de la masse osseuse(2017), Physiopathologie des Maladies du Système Nerveux Central, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Evolution des régulations endocriniennes (ERE), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Analyse d'Images quantitatives (AIQ), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
[SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Central nervous system, Motility, Adipose tissue, Open field, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Marble burying, 03 medical and health sciences, 0302 clinical medicine, longevity, Dlx5/Dlx6, Brown adipose tissue, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, GABAergic neurons, behavior, aging, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Cell Biology, DLX6, DLX5, Cell biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, medicine.anatomical_structure, embryonic structures, biology.protein, GABAergic, Homeobox, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Homeostasis, 030217 neurology & neurosurgery, Parvalbumin, Research Paper
Abstract

Dlx5andDlx6encode two homeobox transcription factors expressed by developing and mature GABAergic interneurons. During developmentDlx5/6are important for the differentiation ofParvalbumin(Pvalb)-expressing neurons. Perinatal lethality of homozygous mice in whichDlx5/6have been constitutively deleted has, so far, hindered the study of the function of these genes in adult neurons. We first show thatDlx5andDlx6are expressed by all subclasses of adult cortical GABAergic neurons. Then we analyseVgatΔDlx5-6mice in whichDlx5andDlx6are simultaneously inactivated in all GABAergic interneurons.VgatΔDlx5-6mice present a behavioral pattern suggesting reduction of anxiety and obsessive-compulsive activities. They rapidly access and spend more time in the central region of an open field, bury few marbles in the marble burying test and show little interest in nest building. Male and female 20-month-oldVgatΔDlx5-6animals have the same size as their normal littermates, but present a 25% body weight reduction associated with a marked decline in white and brown adipose tissue. Remarkably, bothVgatΔDlx5-6/+andVgatΔDlx5-6mice present a 33% longer median survival than their control littermates. Hallmarks of biological aging such as motility, adipose deposition and coat conditions are improved in mutant animals. Our data imply that GABAergic interneurons can regulate mammalian healthspan and lifespan throughDlx5/6-dependent mechanisms. Understanding these regulations can be an entry point to unravel the processes through which the brain affects body homeostasis and, ultimately, longevity and healthy aging.SIGNIFICANCE STATEMENTDlx5 and Dlx6 are transcription factors controlling several developmental processes, including GABAergic neuronal migration and differentiation. To study their function in adult brain, we selectively inactivated both genes in GABAergic interneurons (VgatΔDlx5-6mice). Mutant mice have reduced anxiety-like and obsessive-compulsive behaviors. Interestingly,VgatΔDlx5-6mice have a 25% body weight reduction and about 70% less white and brown adipose tissue; their general health status is excellent.VgatΔDlx5-6mice have a median survival about 33% longer than their control littermates and hallmarks of biological aging are improved. Dlx5/6-dependent regulations in GABAergic neurons could be an entry point to understand how the brain determines the psychophysiological status of the body and, ultimately, longevity and healthy aging.

Published
2019
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4. Probing the origin of matching functional jaws: roles of Dlx5/6 in cranial neural crest cells

Author

Giovanni Levi, Yukiko Kurihara, Yumiko Kawamura, Camille de Lombares, Miki Shimizu, Hiroki Kurihara, Lindsey Marshall, Nicolas Narboux-Nême, Hiroki Higashiyama, Yorick Gitton, Gladys Alfama, Eglantine Heude, Taro Kitazawa, Anastasia Fontaine, Youichiro Wada, Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Heude, Eglantine, Nouvelles cibles pour l'ostéoporose: des cellules souches mésenchymateuses à la régulation de l'ostéogénèse et de la masse osseuse - - TARGETBONE2017 - ANR-17-CE14-0024 - AAPG2017 - VALID, Association métabolisme/cognition : nouvelles voies de régulation impliquant les neurones GABAergiques - - METACOGNITION2017 - ANR-17-CE37-0007 - AAPG2017 - VALID, Health and the Understanding of Metabolism, Aging and Nutrition - HUMAN - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602757 - VALID, Department of Physiological Chemistry and Metabolism [Tokyo, Japan], The University of Tokyo (UTokyo), Isotope Science Center and Research Center for Advanced Science and Technology [Tokyo, Japan], Core Research for Evolutional Science and Technology [Tokyo, Japan] (CREST), Japan Science and Technology Agency (JST), This research was partially supported by the EU Consortium HUMAN (EU-FP7-HEALTH-602757) and by the ANR grants TARGETBONE (ANR-17-CE14-0024) and METACOGNITION (ANR-17-CE37-0007) to GL, and an ATM grant (FORMs) to YG, CdL is supported by a grant of the French Ministry of Research. This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (15H02536) and Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST), Japan (JPMJCR13W2)., ANR-17-CE14-0024,TARGETBONE,Nouvelles cibles pour l'ostéoporose: des cellules souches mésenchymateuses à la régulation de l'ostéogénèse et de la masse osseuse(2017), ANR-17-CE37-0007,METACOGNITION,Association métabolisme/cognition : nouvelles voies de régulation impliquant les neurones GABAergiques(2017), European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of Tokyo, and Evolution des régulations endocriniennes [2009–2018] (ERE)

Subjects
0301 basic medicine, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV]Life Sciences [q-bio], lcsh:Medicine, Mandible, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, Cranial neural crest, 0302 clinical medicine, Maxilla, lcsh:Science, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, 0303 health sciences, Multidisciplinary, First pharyngeal arch, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Neural crest, Gene Expression Regulation, Developmental, DLX5, Cell biology, medicine.anatomical_structure, Neural Crest, embryonic structures, Cell type, Morphogenesis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, 03 medical and health sciences, stomatognathic system, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, [SDV.BID.EVO] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Animals, Craniofacial, Transcription factor, Mastication, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, lcsh:R, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Embryonic stem cell, Mice, Mutant Strains, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, stomatognathic diseases, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, lcsh:Q, Developmental biology, 030217 neurology & neurosurgery
Abstract

SUMMARYGnathostome jaws derive from the first pharyngeal arch (PA1), a complex structure constituted by Neural Crest Cells (NCCs), mesodermal, ectodermal and endodermal cells. Here, to determine the regionalized morphogenetic impact ofDlx5/6expression, we specifically target their inactivation or overexpression to NCCs. NCC-specificDlx5/6inactivation (NCCΔDlx5/6) generates severely hypomorphic lower jaws that present typical maxillary traits. Therefore, differently from the symmetric jaws obtained after constitutiveDlx5/6inactivation,NCCΔDlx5/6embryos present a strikingly asymmetric mouth. Reciprocally, forcedDlx5expression in maxillary NCCs provokes the appearance of distinct mandibular characters in the upper jaw. We conclude that: 1)Dlx5/6activation in NCCs invariably determines lower jaw identity; 2) the morphogenetic processes that generate functional matching jaws depend on the harmonization ofDlx5/6expression in NCCs and in distinct ectodermal territories. The co-evolution of synergistic opposing jaws requires the coordination of distinct regulatory pathways involving the same transcription factors in distant embryonic territories.

Published
2018
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5. Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis

Author

Luca Mastracci, Nicolas Narboux-Nême, Paolo Garagnani, Anne Bachelot, Evelyne Duvernois-Berthet, Anastasia Fontaine, Ottavia Barbieri, Giovanni Levi, Chiara Pirazzini, Brice Bellessort, Gladys Alfama, Marine Le Cardinal, Vincent Jonchere, Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Endocrinologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Experimental Medicine, University of Genova, Istituto Nazionale per la Ricerca sul Cancro, Universita degli studi di Genova, Department of Anatomic Pathology, Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Genova = University of Genoa (UniGe), Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Muséum national d'Histoire naturelle (MNHN), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Levi, Giovanni

Subjects
0301 basic medicine, Mullerian Ducts, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Endometriosis, Uterus, Biology, Endometrium, Epithelium, Andrology, 03 medical and health sciences, Mice, Downregulation and upregulation, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Homeobox, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Embryo Implantation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Molecular Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Homeodomain Proteins, Leydig cell, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genes, Homeobox, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, General Medicine, medicine.disease, Molecular biology, 030104 developmental biology, medicine.anatomical_structure, Genes, Gene Expression Regulation, In utero, embryonic structures, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Transcriptome
Abstract

Dlx5 and Dlx6 are two closely associated homeobox genes which code for transcription factors involved in the control of steroidogenesis and reproduction. Inactivation of Dlx5/6 in the mouse results in a Leydig cell defect in the male and in ovarian insufficiency in the female. DLX5/6 are also strongly expressed by the human endometrium but their function in the uterus is unknown. The involvement of DLX5/6 in human uterine pathology is suggested by their strong downregulation in endometriotic lesions and upregulation in endometrioid adenocarcinomas. We first show that Dlx5/6 expression begins in Mullerian ducts epithelia and persists then in the uterine luminal and glandular epithelia throughout post-natal maturation and in the adult. We then use a new mouse model in which Dlx5 and Dlx6 can be simultaneously inactivated in the endometrium using a Pgr(cre/+) allele. Post-natal inactivation of Dlx5/6 in the uterus results in sterility without any obvious ovarian involvement. The uteri of Pgr(cre/+); Dlx5/6(flox/flox) mice present very few uterine glands and numerous abnormally large and branched invaginations of the uterine lumen. In Dlx5/6 mutant uteri, the expression of genes involved in gland formation (Foxa2) and in epithelial remodelling during implantation (Msx1) is significantly reduced. Furthermore, we show that DLX5 is highly expressed in human endometrial glandular epithelium and that its expression is affected in endometriosis. We conclude that Dlx5 and Dlx6 expression determines uterine architecture and adenogenesis and is needed for implantation. Given their importance for female reproduction, DLX5 and DLX6 must be regarded as interesting targets for future clinical research.

Published
2015
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6. Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome

Author

Giovanni Levi, Anastasia Fontaine, Manatsu Hamazaki, Brice Bellessort, Eglantine Heude, Nicolas Narboux-Nême, Anna-Corina Treier, Mathias Treier, Genetic of Metabolic and Reproductive Disorders, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Département Adaptations du vivant (AVIV), and Muséum national d'Histoire naturelle (MNHN)

Subjects
Forkhead Box Protein L2, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Blepharophimosis, Extraocular muscles, Craniofacial Abnormalities, Mice, Cranial neural crest, Ptosis, Genetics, medicine, Animals, Craniofacial, 10. No inequality, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Genetic disorder, Eyelids, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Forkhead Transcription Factors, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, General Medicine, Anatomy, medicine.disease, medicine.anatomical_structure, Forkhead box L2, Oculomotor Muscles, Urogenital Abnormalities, Skin Abnormalities, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Eyelid, medicine.symptom, Gene Deletion
Abstract

Blepharophimosis, ptosis, epicanthus-inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by narrow palpebral fissures and eyelid levator muscle defects. BPES is often associated to premature ovarian insufficiency (BPES type I). FOXL2, a member of the forkhead transcription factor family, is the only gene known to be mutated in BPES. Foxl2 is essential for maintenance of ovarian identity, but the developmental origin of the facial malformations of BPES remains, so far, unexplained. In this study, we provide the first detailed account of the developmental processes leading to the craniofacial malformations associated to Foxl2. We show that, during development, Foxl2 is expressed both by Cranial Neural Crest Cells (CNCCs) and by Cranial Mesodermal Cells (CMCs), which give rise to skeletal (CNCCs and CMCs) and muscular (CMCs) components of the head. Using mice in which Foxl2 is selectively inactivated in either CNCCs or CMCs, we reveal that expression of Foxl2 in CNCCs is essential for the development of extraocular muscles. Indeed, inactivation of Foxl2 in CMCs has only minor effects on muscle development, whereas its inactivation in CNCCs provokes a severe hypoplasia of the levator palpabrae superioris and of the superior and inferior oblique muscles. We further show that Foxl2 deletion in either CNCCs or CMCs prevents eyelid closure and induces subtle skeletal developmental defects. Our results provide new insights in the complex developmental origin of human BPES and could help to understand the origin of other ocular anomalies associated to this syndrome.

Published
2015
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7. Role of Foxl2 in uterine maturation and function

Author

A. Bachelot, Gladys Alfama, Eglantine Heude, Marine Le Cardinal, Brice Bellessort, Giovanni Levi, Mathias Treier, Anastasia Fontaine, Heude, Eglantine, Integrated research on DEvelopmental determinants of Aging and Longevity - IDEAL - - EC:FP7:HEALTH2011-02-01 - 2016-01-31 - 259679 - VALID, Health and the Understanding of Metabolism, Aging and Nutrition - HUMAN - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602757 - VALID, Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Genetics of Metabolic and Reproductive Disorders [Berlin, Germany], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association-Helmholtz-Gemeinschaft = Helmholtz Association, This research was partially supported by the EU Consortia IDEAL (HEALTH-F2-2011-259679) and HUMAN (EU-FP7-HEALTH-602757)., European Project: 259679,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,IDEAL(2011), European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Laboratoire de Physiologie Générale et Comparée (LPGC), Centre National de la Recherche Scientifique (CNRS), Endocrinologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), and European Molecular Biology Laboratory [Heidelberg] (EMBL)

Subjects
Forkhead Box Protein L2, Male, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Uterus, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 0302 clinical medicine, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), 0303 health sciences, 030219 obstetrics & reproductive medicine, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Myometrium, Forkhead Transcription Factors, General Medicine, medicine.anatomical_structure, Forkhead box L2, Organ Specificity, Oviduct, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Infertility, Female, medicine.medical_specialty, Stromal cell, Mice, Transgenic, Ovary, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, 03 medical and health sciences, Internal medicine, FLOX, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, [SDV.BID.EVO] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Animals, Adenomyosis, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Genetic Association Studies, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle, Smooth, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Mice, Inbred C57BL, Endocrinology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis
Abstract

International audience; Foxl2 codes for a forkhead/HNF3 transcription factor essential for follicular maturation and maintenance of ovarian identity. FOXL2 mutations are associated with Blepharophimosis, Ptosis and Epicanthus inversus Syndrome (BPES) characterized by eyelid malformations (types I and II) and premature ovarian insufficiency (type I). We show that Foxl2 is not only expressed by the ovary, but also by other components of the mouse female reproductive tract, including the uterus, the cervix and the oviduct. In the uterus, Foxl2 expression is first observed in the neonatal mesenchyme and, during uterine maturation, persists in the stroma and in the deep inner myometrial layer (IML). In the adult, Foxl2 is expressed in the differentiated stromal layer, but no longer in the myometrium. Conditional deletion of Foxl2 in the postnatal (PN) uterus using Progesterone Receptor-cre (Pgr(cre/+)) mice results in infertility. During PN uterine maturation Pgr(cre/+); Foxl2(flox/flox) mice present a severely reduced thickness of the stroma layer and an hypertrophic, disorganized IML. In adult Pgr(cre/+); Foxl2(flox/flox) mice a supplementary muscular layer is present at the stroma/myometrium border and vascular smooth muscle cells fail to form a coherent layer around uterine arteries. Wnt signalling pathways play a central role in uterine maturation; in Pgr(cre/+); Foxl2(flox/flox) mice, Wnt genes are deregulated suggesting that Foxl2 acts through these signals. In humans, thickening of the IML (also called "junctional zone") is associated with reduced fertility, endometriosis and adenomyosis. Our data suggest that Foxl2 has a crucial role in PN uterine maturation and could help to understand sub-fertility predisposition in women.

Published
2015
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8. Identification de nouvelles cibles moléculaires dans l’endométriose

Author

N. Narboux Neme, E. Duvernois, Giovanni Levi, Gladys Alfama, Anastasia Fontaine, A. Bachelot, C. De Rimonteil De Lombares, V. Grouthier, and B. Bellesort

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, General Medicine
Abstract

Objectif Les genes codant pour les facteurs de transcriptions DLX5 et DLX6 sont fortement sous-exprimes au sein des lesions d’endometriose par rapport a l’endometre normal (Hawkins et al., 2011, Hever et al., 2007, Hu et al., 2006). Nous avons montre qu’une inactivation dans l’uterus de Dlx5 et Dlx6 chez la souris aboutit a une histologie similaire a certaines lesions endometriosiques (Bellessort et al., 2016). Nous avons compare le profil d’expression des genes dans les lesions endometriosiques chez la femme a ceux de l’uterus de souris inactivees pour Dlx5 et Dlx6. Resultats Nous avons identifie 22 genes deregules de maniere identique dans la souris et dans les lesions endometriosiques confirmant une signature moleculaire commune. Nous avons en particulier repere que CACNA2D3, un composant d’un canal calcique voltage-dependant, est fortement surexprime, dans les uterus de souris mutantes comme dans les lesions d’endometriose. CACNA2D3 a ete associe a la nociception dans des modeles animaux et chez l’homme (Neely et al., 2010). Discussion Notre etude montre a permis de mettre en evidence que CACNA2D3, fortement surexprime dans les uterus de souris inactivees pour Dlx5 et Dlx6 et dans les lesions d’endometriose chez la femme. Sa presence dans les lesions endometriosiques pourrait etre associee aux douleurs pelviennes chroniques specifiques de cette pathologie et suggererait une cible therapeutique potentielle.

Published
2017
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9. Étude des gènes Dlx5/6 dans le développement et la fonction de l’utérus chez la souris

Author

A. Bachelot, Nicolas Narboux-Nême, Gladys Alfama, Anastasia Fontaine, Giovanni Levi, B. Bellesort, and M. Le Cardinal

Subjects
Endocrinology, Endocrinology, Diabetes and Metabolism, embryonic structures, General Medicine
Abstract

Contexte Dlx5 et Dlx6 sont deux facteurs de transcription qui jouent un role important dans le controle de la morphogenese et la differenciation cellulaire. Des donnees preliminaires ont montre la presence de ces facteurs dans l’uterus chez la souris. Objectifs Etude de Dlx5 et Dlx6 au cours du developpement de l’uterus chez la souris. Materiel et methodes Le profil d’expression a ete realise grâce aux souris Dlx5/6 LacZ/+ et par immuno-histochimie. L’inactivation specifique de Dlx5 et Dlx6 dans l’uterus a ete realise par croisement des souris invalides pour ces genes avec une lignee porteuse du gene de la recombinase-cre sous controle du promoteur du recepteur de la progesterone. Resultats Dlx5 et Dlx6 sont exprimes dans l’epithelium des canaux de Muller des le stade embryonnaire a partir de E15.5 et que leur expression persiste dans l’epithelium glandulaire tout au long de maturation postnatale chez l’adulte. Les souris femelles Pgr cre / + ; Dlx5/6 flox / flox sont steriles. L’etude en histologie de leur uterus montre la presence en tres faible nombre de glandes uterines. L’analyse par qPCR de l’uterus de ces souris retrouve une expression augmentee de Wnt7a, qui joue un role dans la formation des glandes, tandis que celle de Msx1, implique dans les modifications epitheliales lors de l’implantation, est reduite. Discussion Nos donnees suggerent que Dlx5 et Dlx6 jouent un role important chez la souris dans la generation des glandes uterines, necessaires chez l’adulte a l’implantation de l’embryon.

Published
2015
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