TEAM

Transcriptional regulatory networks in development and diseases

Group leader : L. Fasano

Our laboratory aims to understand the mechanisms that control normal development and how their deregulation causes disease, with a particular interest in autism spectrum disorders.

FOR BEGINNERS

Our laboratory aims to understand the mechanisms that control normal development and how their deregulation causes disease, with a particular interest in autism spectrum disorders (ASD).

ASD is a heterogeneous group of neurodevelopmental pathologies characterized by impairments in social interaction and stereotypies. Although the rates of ASD diagnosis are increasing, there is no treatments for the core ASD symptoms. New therapeutic strategies to improve them are thus needed.

We previously linked the human TSHZ3 gene to a new ASD syndrome (19q12DS) and elucidated some of its molecular, cellular and synaptic mechanisms by using different Tshz3 mouse models. This initial work points to cortical and corticostriatal circuitry dysfunctions in TSHZ3-related ASD, and identifies the early postnatal period of cortical development as a critical phase for this pathology.

Our main objective is to gain more knowledge onto “where” and “when” Tshz3 is essential for the development and function of the corticostriatal circuitry in relationship with ASD, as basis for the research of novel treatment strategies. To do so, we are characterizing new Tshz3 mouse models.

Our paper in Biological Psychiatry (Postnatal Tshz3 deletion drives altered corticostriatal function and ASD-like behavior) links postnatal loss of Tshz3 gene and Autism Spectrum Disorder.

Our paper in Biological Psychiatry (Postnatal Tshz3 deletion drives altered corticostriatal function and ASD-like behavior) links postnatal loss of Tshz3 gene and Autism Spectrum Disorder.

FOR SPECIALISTS

Our laboratory aims to understand the mechanisms that control normal development and how their deregulation causes disease, with a particular interest in autism spectrum disorders (ASD).

ASD is a heterogeneous group of neurodevelopmental pathologies characterized by impairments in social interaction and stereotypies. Although the rates of ASD diagnosis are increasing, there is no treatments for the core ASD symptoms. New therapeutic strategies to improve them are thus needed.

We previously linked the human TSHZ3 gene to a new ASD syndrome (19q12DS) and elucidated some of its molecular, cellular and synaptic mechanisms by using different Tshz3 mouse models. In these models, heterozygous (Tshz3+/lacZ model) and postnatal (Camk2a-cKO model) deletion of Tshz3 in the brain leads to ASD-like phenotype, namely impaired social behavior and stereotypies, paralleled with impaired transmission and plasticity at corticostriatal synapses. This initial work points to cortical and corticostriatal circuitry dysfunctions in TSHZ3-related ASD, and identifies the early postnatal period of cortical development as a critical phase for this pathology.

On our publication in Nature Genetics we identified a module of genes co-expressed with TSHZ3 in the human neocortex at mid gestation, which is enriched for ASD-associated genes (blue “balls”).

On our publication in Nature Genetics we identified a module of genes co-expressed with TSHZ3 in the human neocortex at mid gestation, which is enriched for ASD-associated genes (blue “balls”).

A major goal is to better understand how deletion of the TSHZ3 gene leads to the appearance of the ASD core symptoms. To address this question, our team developed mouse models allowing targeted conditional deletion of Tshz3. We use this strategy to delete Tshz3 in two components of the corticostriatal circuitry: the cortical projection neurons (CPNs) and the striatal cholinergic interneurons (SCINs).

We also generated a conditional rescue mouse model to determine whether the timely-controlled restoration of Tshz3 expression in CPNs and/or SCINs can improve ASD symptoms. This approach was stimulated by the fact that the viability of Tshz3 mutant neurons is not affected incorticostriatal circuits, raising the promising issue of rescuing postnatally the ASD phenotype. We are characterizing this conditional rescue mouse model.

TSHZ3 protein (red) is expressed at high levels by cortical projection neurons in deep-layer of the mouse cerebral cortex.

TSHZ3 protein (red) is expressed at high levels by cortical projection neurons in deep-layer of the mouse cerebral cortex.

 


Selected publications

PUBLICATION

Regulation of the positive transcriptional effect of PLZF through a non-canonical EZH2 activity

Myriam Kombi, Mathilde Poplineau, Julien Vernerey, Lia N'Guyen, Guillaume Tiberi, Sylvain Garciaz, Abdessamad El-Kaoutari, Muhammad A Maqbool, Jean-Christophe Andrau, Christel Guillouf, Andrew J Saurin, Estelle Duprez
Nucleic Acids Res . 2018 Apr 20;46(7):3339-3350. doi: 10.1093/nar/gky080 PMID: 29425303

PUBLICATION

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.

Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M1, Jacq B, Fatmi A, Had-Aissouni L, Kwan KY, Salin P, Carlier M, Liedén A, Rudd E, Shinawi M, Vincent-Delorme C, Cuisset JM, Lemaitre MP10, Abderrehamane F, Duban B, Lemaitre JF, Woolf AS, Bockenhauer D, Severac D, Dubois E, Zhu Y, Sestan N, Garratt AN, Kerkerian-Le Goff L, Fasano L.
Nat Genet. 2016 Sep 26. PMID: 27668656

PUBLICATION

The tiptop/teashirt genes regulate cell differentiation and renal physiology in Drosophila.

Denholm B, Hu N, Fauquier T, Caubit X, Fasano L, Skaer H.
Development. 2013 Mar;140(5):1100-10. PMID: 23404107

PUBLICATION

Teashirt 3 regulates development of neurons involved in both respiratory rhythm and airflow control.

Caubit X, Thoby-Brisson M, Voituron N, Filippi P, Bévengut M, Faralli H, Zanella S, Fortin G, Hilaire G, Fasano L.
J Neurosci. 2010 Jul 14;30(28):9465-76. PMID: 20631175

PUBLICATION

Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4.

Caubit X, Lye CM, Martin E, Coré N, Long DA, Vola C, Jenkins D, Garratt AN, Skaer H, Woolf AS, Fasano L.
Development. 2008 Oct;135(19):3301-10. PMID: 18776146

PUBLICATION

A critical role of teashirt for patterning the ventral epidermis is masked by ectopic expression of tiptop, a paralog of teashirt in Drosophila.

Laugier E, Yang Z, Fasano L, Kerridge S, Vola C.
Dev Biol. 2005 Jul 15;283(2):446-58. PMID: 15936749

PUBLICATION

Expression patterns of the three Teashirt-related genes define specific boundaries in the developing and postnatal mouse forebrain.

Caubit X, Tiveron MC, Cremer H, Fasano L.
J Comp Neurol. 2005 May 23;486(1):76-88. PMID: 15834955

PUBLICATION

Three putative murine Teashirt orthologues specify trunk structures in Drosophila in the same way as the Drosophila teashirt gene.

Manfroid I, Caubit X, Kerridge S, Fasano L.
Development. 2004 Mar;131(5):1065-73. PMID: 14973285

PUBLICATION

Vertebrate orthologues of the Drosophila region-specific patterning gene teashirt.

Caubit X, Coré N, Boned A, Kerridge S, Djabali M, Fasano L.
Mech Dev. 2000 Mar 1;91(1-2):445-8. PMID: 10704881

PUBLICATION

The gene teashirt is required for the development of Drosophila embryonic trunk segments and encodes a protein with widely spaced zinc finger motifs.

Fasano L, Röder L, Coré N, Alexandre E, Vola C, Jacq B, Kerridge S.
Cell. 1991 Jan 11;64(1):63-79. PMID: 1846092

PUBLICATION

TSHZ3 and SOX9 Regulate the Timing of Smooth Muscle Cell Differentiation in the Ureter by Reducing Myocardin Activity.

Martin E, Caubit X, Airik R, Vola C, Fatmi A, Kispert A, Fasano L.
PLoS One. 2013 May 6;8(5):e63721. PMID: 23671695

PUBLICATION

Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.

McBride DJ, Etemadmoghadam D, Cooke SL, Alsop K, George J, Butler A, Cho J, Galappaththige D, Greenman C, Howarth KD, Lau KW, Ng CK,Raine K, Teague J, Wedge DC, Cancer Study Group AO, Caubit X, Stratton MR, Brenton JD, Campbell PJ, Futreal PA, Bowtell DD.
J Pathol. 2012 Aug;227(4):446-55. PMID: 22514011

PUBLICATION

Teashirt in cell proliferation

Silvia Pimentel, Rui Gomes, Laurent Fasano.
Book Chapter. LAP Lambert Academic Publishing (2012-03-23).

PUBLICATION

Toward a new role for plasma membrane sodium-dependent glutamate transporters of astrocytes: maintenance of antioxidant defenses beyond extracellular glutamate clearance.

Had-Aissouni L.
Amino Acids. 2012 Jan;42(1):181-97. PMID: 21399919

PUBLICATION

Maintenance of antioxidant defenses of brain cells: plasma membrane glutamate transporters and beyond.

Had-Aissouni L.
Amino Acids. 2012 Jan;42(1):159-61. PMID: 21394602

PUBLICATION

Oxidative stress and prevention of the adaptive response to chronic iron overload in the brain of young adult rats exposed to a 150 kilohertz electromagnetic field.

Maaroufi K, Save E, Poucet B, Sakly M, Abdelmelek H, Had-Aissouni L.
Neuroscience. 2011 Jul 14;186:39-47. PMID: 21497179

PUBLICATION

Teashirt-3, a novel regulator of muscle differentiation, associates with BRG1-associated factor 57 (BAF57) to inhibit myogenin gene expression.

Faralli H, Martin E, Coré N, Liu QC, Filippi P, Dilworth FJ, Caubit X, Fasano L.
J Biol Chem. 2011 Jul 1;286(26):23498-510. PMID: 21543328

PUBLICATION

Ureter myogenesis: putting Teashirt into context.

Lye CM, Fasano L, Woolf AS.
J Am Soc Nephrol. 2010 Jan;21(1):24-30. PMID: 19926888

PUBLICATION

Analysis of TSHZ2 and TSHZ3 genes in congenital pelvi-ureteric junction obstruction.

Jenkins D, Caubit X, Dimovski A, Matevska N, Lye CM, Cabuk F, Gucev Z, Tasic V,Fasano L, Woolf AS.
Nephrol Dial Transplant. 2010 Jan;25(1):54-60. PMID: 19745106

PUBLICATION

Tshz1 is required for axial skeleton, soft palate and middle ear development in mice.

Coré N, Caubit X, Metchat A, Boned A, Djabali M, Fasano L.
Dev Biol. 2007 Aug 15;308(2):407-20. PMID: 17586487

PUBLICATION

Direct interaction between Teashirt and Sex combs reduced proteins, via Tsh's acidic domain, is essential for specifying the identity of the prothorax in Drosophila.

Taghli-Lamallem O, Gallet A, Leroy F, Malapert P, Vola C, Kerridge S, Fasano L.
Dev Biol. 2007 Jul 1;307(1):142-51. PMID: 17524390

PUBLICATION

Teashirt 3 expression in the chick embryo reveals a remarkable association with tendon development.

Manfroid I, Caubit X, Marcelle C, Fasano L.
Gene Expr Patterns. 2006 Oct;6(8):908-12. http://www.ncbi.nlm.nih.gov/pubmed/16631416Teashirt 3 expression in the chick embryo reveals a remarkable association with tendon development.

PUBLICATION

Chaetognath phylogenomics: a protostome with deuterostome-like development.

Salvioli B, Belmonte G, Stanghellini V, Baldi E, Fasano L, Pacilli AM, De Giorgio R, Barbara G, Bini L, Cogliandro R, Fabbri M, Corinaldesi R.
Curr Biol. 2006 Aug 8;16(15):R577-8. PMID: 16890510

PUBLICATION

Restricted expression of a median Hox gene in the central nervous system of chaetognaths.

Papillon D, Perez Y, Fasano L, Le Parco Y, Caubit X.
Dev Genes Evol. 2005 Jul;215(7):369-73. PMID: 15789247

PUBLICATION

Hox gene survey in the chaetognath Spadella cephaloptera: evolutionary implications.

Papillon D, Perez Y, Fasano L, Le Parco Y, Caubit X.
Dev Genes Evol. 2003 Apr;213(3):142-8. PMID: 12690453

PUBLICATION

Characterisation of set-1, a conserved PR/SET domain gene in Caenorhabditis elegans.

Terranova R, Pujol N, Fasano L, Djabali M.
Gene. 2002 Jun 12;292(1-2):33-41. PMID: 12119097

PUBLICATION

Grunge, related to human Atrophin-like proteins, has multiple functions in Drosophila development.

Erkner A, Roure A, Charroux B, Delaage M, Holway N, Coré N, Vola C, Angelats C, Pagès F, Fasano L, Kerridge S.
Development. 2002 Mar;129(5):1119-29. PMID: 11874908

PUBLICATION

Cubitus interruptus acts to specify naked cuticle in the trunk of Drosophila embryos.

Angelats C, Gallet A, Thérond P, Fasano L, Kerridge S.
Dev Biol. 2002 Jan 1;241(1):132-44. PMID: 11784100

PUBLICATION

Characterization of the two zebrafish orthologues of the KAL-1 gene underlying X chromosome-linked Kallmann syndrome.

Ardouin O, Legouis R, Fasano L, David-Watine B, Korn H, Hardelin J, Petit C.
Mech Dev. 2000 Jan;90(1):89-94. PMID: 10585565

PUBLICATION

The role of Teashirt in proximal leg development in Drosophila: ectopic Teashirt expression reveals different cell behaviours in ventral and dorsal domains.

Erkner A, Gallet A, Angelats C, Fasano L, Kerridge S.
Dev Biol. 1999 Nov 15;215(2):221-32. PMID: 10545232

PUBLICATION

The levels of the bancal product, a Drosophila homologue of vertebrate hnRNP K protein, affect cell proliferation and apoptosis in imaginal disc cells.

Charroux B, Angelats C, Fasano L, Kerridge S, Vola C.
Mol Cell Biol. 1999 Nov;19(11):7846-56. PMID: 10523673

PUBLICATION

The C-terminal domain of armadillo binds to hypophosphorylated teashirt to modulate wingless signalling in Drosophila.

Gallet A, Angelats C, Erkner A, Charroux B, Fasano L, Kerridge S.
EMBO J. 1999 Apr 15;18(8):2208-17. PMID: 10205174

PUBLICATION

Trunk-specific modulation of wingless signalling in Drosophila by teashirt binding to armadillo.

Gallet A, Erkner A, Charroux B, Fasano L, Kerridge S.
Curr Biol. 1998 Jul 30-Aug 13;8(16):893-902. PMID: 9707400

PUBLICATION

Transcriptional regulation of the Drosophila homeotic gene teashirt by the homeodomain protein Fushi tarazu.

Coré N, Charroux B, McCormick A, Vola C, Fasano L, Scott MP, Kerridge S.
Mech Dev. 1997 Nov;68(1-2):157-72. PMID: 9431813

PUBLICATION

GIF-DB, a WWW database on gene interactions involved in Drosophila melanogaster development.

Jacq B, Horn F, Janody F, Gompel N, Serralbo O, Mohr E, Leroy C, Bellon B, Fasano L, Laurenti P, Röder L.
Nucleic Acids Res. 1997 Jan 1;25(1):67-71. PMID: 9016506

PUBLICATION

The Drosophila teashirt homeotic protein is a DNA-binding protein and modulo, a HOM-C regulated modifier of variegation, is a likely candidate for being a direct target gene.

Alexandre E, Graba Y, Fasano L, Gallet A, Perrin L, De Zulueta P, Pradel J, Kerridge S, Jacq B.
Mech Dev. 1996 Oct;59(2):191-204. PMID: 8951796

PUBLICATION

Monitoring positional information during oogenesis in adult Drosophila.

Fasano L, Kerridge S.
Development. 1988 Oct;104(2):245-53 PMID: 2855515

Interactions

IBDM
  • Lydia Kerkerian – Le Goff : functional characterisation of Tshz3 mutant mice in collaboration with Paolo Gubellini and Jordan Molitor (PhD)
  • Bianca Habermann : Bioinformatics analysis of Omics data obtained from different Tshz3 mouse models
INTERNATIONAL
  • Adrian Woolf, Manchester Biomedical Research Centre, UK
  • Marwan Shinawi, Washington University School of Medicine, USA

Funding

ANR

Programme-europeen

Coordinateur du PhD programme Européen RENALTRACT de 2015 à 2018

Members more

    Xavier Caubit Ahmed Fatmi  
Laurent Fasano
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Laurent Fasano

Researcher

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camille Pourcet-boulay

Trainee

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Elise Arbeille

Researcher

Xavier Caubit
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Xavier Caubit

University lecturer

Ahmed Fatmi
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Ahmed Fatmi

Technical staff

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Laurence Had

University lecturer

Alumni

  • Irene Sanchez-Martin, PhD 2015-2018, Post-doc at Icahn School of Medicine at Mount Sinai, NY, USA
  • Teddy Fauquier, Postdoc 2011-2012 ; Ingineer, MMG UMR1251, Marseille France, teddy.fauquier@univ-amu.fr
  • Silvia Pimentel, PhD 2008-2010 ;
  • Elise Martin, PhD 2006-2010 ; Teacher
  • Hervé Faralli, PhD 2006-2009 ; Hôpital Européen, Marseille, France
  • Edith Laugier, PhD 2003-2005 ;
  • Isabelle Manfroid, Postdoc 2001-2004 ; Chercheur, Université de Liège; Isabelle.Manfroid@uliege.be
  • Ouarda Taghli-Lamalem, PhD 1999-2001 ;
  • Corinne Angelats, PhD 1998-2000 ; Teacher
  • Armel Gallet, PhD 1996-1999 ; CNRS Researcher, Institut Sophia Agrobiotech, armel.gallet@unice.fr
  • Nathalie Coré ; CNRS Researcher, IBDM, Marseille, France, Nathalie.core@univ-amu.fr
  • Frédéric Leroy ; CNRS ingineer, IBDM, Marseille, France, Frederic.leroy@univ-amu.fr
  • Pascale Malapert ; CNRS ingineer, IBDM, Marseille, France, pascale.malapert@univ-amu.fr

Overview

Animal model organism
Biological process studied
  • Brain & kidney development
Biological techniques
  • Molecular Biology
  • Cellular Biology
  • Confocal & elctron microscopy
  • Omics
  • Anathomopathology
  • Behavioral testing
  • PCR – qRT-PCR
  • In situ
  • Immunohistochemistry
Medical applications
  • Autism