TEAM

Molecular mechanisms underlying mesenchymal cell differentiation

Group leader : L. Fasano

Our work will allow a better understanding of the genetic and molecular basis of congenital visceral smooth muscle malformations.

FOR BEGINNERS

Smooth muscles, unlike skeletal muscle, contract slowly and involuntarily (spontaneous contractile activity). These smooth muscles are found in vascular walls, digestive, respiratory and urinary tract. Their function is to assist in the transport of various media (i.e. blood for blood vessels, air in the bronchi, urine in ureters).

During embryonic development, differentiation of smooth muscle cells is a crucial process for the development of blood vessels and hollow organs (eg intestine, ureter, lungs). Alterations of this mechanism contribute to the development of various diseases such as atherosclerosis, hypertension or asthma.

We showed in mice that the transcription factor TSHZ3 played a key role in the differentiation of ureteral mesenchyme into smooth muscle. Work in progress will allow a better understanding of the genetic and molecular basis of congenital visceral smooth muscle malformations.

We also highlighted the importance of TSHZ3 in the establishment of the neural circuit that controls breathing. Tshz3 is a candidate gene for childhood respiratory defects in humans.

FOR SPECIALISTS

Tshz3 gene codes for a zinc finger transcription factor (TSHZ3) (Caubit et al., 2000) involved in several developmental processes in the ureter, the central nervous system and skeletal muscle (Caubit et al., 2008 , Caubit et al., 2010; Faralli et al., 2011).

1. Morphogenesis of the ureter involves reciprocal interactions between the epithelial and the mesenchymal compartment. Mesenchymal cells contribute to the formation of smooth muscles wich are essential to carry dynamically the urine produced by the kidney to the bladder. Tshz3LacZ/LacZ mutant mice die at birth and exhibit a phenotype of hydroureter (Figure 1). Picture of Tshz3 mutant mice with a phenotype of hydroureter by the Fasano Team from IBDM, IBDML

Analysis of Tshz3LacZ/LacZ embryos showed that the ureter mesenchyme does not differentiate into smooth muscle. We have shown that the factor TSHZ3 is required downstream of SHH and BMP4 signaling pathways and upstream the “master” transcription factor Myocardin for differentiation of smooth muscle cells (Caubit et al., 2008, Lye et al., 2010 ) (Figure 2 and 3).

pic-2

Defects observed in the Tshz3LacZ/LacZ mutant mice are comparable to those observed in patients with obstruction of the ureteropelvic junction. Smooth muscle cells present the particularity to move along a continuum between two extremes: a proliferative state during development to a highly differentiated and contractile state. The transcriptional mechanisms that confer this phenotypic plasticity remain largely misunderstood. Our work is underway to better describe the transcriptional mechanisms involved in the different stages of the myogenic program.

pic-3

2. In collaboration with researchers from the University of Aix-Marseille and Paris-Sud 11, we have shown that Tshz3 is a gene required for breathing and therefore, for survival at birth (Caubit et al. 2010) (Figure 4).

pic-4

In mammals, fetus develops in a liquid environment where the umbilical cord provides oxygen and pulmonary functions are virtually absent. At birth, the baby transitions from aquatic intrauterine life to autonomy in the air. How does the body prepare to such a brutal transition? We already know that several neuronal circuits are involved in neonatal respiration in mammals. More specifically, two regions in the hindbrain have been identified (préBötzinger complex and para-facial respiratory group). These neurons initiate a pacemaker activity, that is to say, a rhythm in the brain stem initiating automatic respiratory movements and preparing newborns to birth. Our work shows that TSHZ3 is expressed in the para-facial respiratory group and plays a major role in the neuronal activity of this region. Tshz3LacZ/LacZ mutant newborn mice do not breathe at birth and die after a few minutes. In these newborn (Tshz3LacZ/LacZ mutant), preBötzinger complex and para-facial respiratory group seems to be correctly formed but neurons from the para-facial respiratory group do not exhibit their characteristic  rhythmic activity (Figure 5).

In Tshz3LacZ/LacZ mutant, neurons from the para-facial respiratory group do not exhibit their characteristic rhythmic activity by the Fasano Team from IBDM, IBDML

Figure 5

Thus, a single gene, Tshz3 is able to control at the level of neurons, the development of several elements and cellular events that are critical for the acquisition of breathing at birth. In the future, collaboration with medical research teams could bring a better understanding of the implication of Tshz3 in human respiratory disorders, from sleep apnea syndrome to sudden infant death syndrome, the leading cause mortality of newborns in Western countries. Through this work, we have also shown that Tshz3 is required for the survival of motor neurons of the nucleus ambiguus.

Work in progress aims to better characterize the role of TSHZ3 factor in the differentiation and/or survival process of different neuronal populations in the central nervous system.


Main publications

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
Other publications

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

Interactions with technical facilities (mice houses, informatics and imagery)

NATIONAL
  • Andreas Schedl, INSERM U636, Nice
  • Joris Andrieux, 
Institut de Génétique Médicale 
CHRU de Lille, France
  • Pierre Roubertoux, INSERM U910, Marseille
INTERNATIONAL
  • Franz Schaefer, Head, Division of Pediatric Nephrology and KFH Children’s Kidney Center, Heidelberg University Medical Center, Germany
  • Adrian Woolf, Manchester Biomedical Research Centre, UK
  • Andreas Kispert, Institut für Molekularbiologie, Medizinische Hoshscule Hannover, Germany
  • Helen Skaer, Department of Zoology, DowningStreet, Cambridge, UK
  • Allistair Garrat, Max-Delbrück Center, Berlin, German
  • Agne Liedén, Karolinska University Hospital, Clinical Genetics Unit, Sweden
  • Marwan Shinawi, Washington University School of Medicine, USA
  • Kenneth Kwan and Nenad Sestan, Department of Neurobiology, Yale University, USA

Members more

Xavier Caubit Ahmed Fatmi Laurence Had Aissouni Irene Sanchez Martin Dimitri Stojanovic
Laurent Fasano
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Laurent Fasano

Researcher

Xavier Caubit
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Xavier Caubit

University lecturer

Ahmed Fatmi
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Ahmed Fatmi

Technical staff

Laurence Had Aissouni
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Laurence Had Aissouni

University lecturer

Irene Sanchez Martin
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Irene Sanchez Martin

PhD student

Dimitri Stojanovic
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Dimitri Stojanovic

Technical staff

Alumni

  • Teddy Fauquier, Postdoc 2011-2012
  • Silvia Pimentel, PhD 2008-2010
  • Elise Martin, PhD 2006-2010
  • Hervé Faralli, PhD 2006-2009
  • Edith Laugier, PhD 2003-2005
  • Isabelle Manfroid, Postdoc 2001-2004
  • Ouarda Taghli-Lamalem, PhD 1999-2001
  • Corinne Angelats, PhD 1998-2000
  • Armel Gallet, PhD 1996-1999
  • Nathalie Coré
  • Pierre Filippi
  • Christine Vola
  • Frédéric Leroy
  • Pascale Malapert

Overview

Animal model organism
Biological process studied
  • Molecular mechanisms underlying mesenchymal cell differentiation
Biological techniques
  • Behavioral Tests
  • Cellular and molecular biology
  • PCR and qRT-PCR
  • In situ hybridization
  • Immunohistochemistry
  • Protein-protein interaction tests
  • In vivo and in vitro analysis of regulation of gene expression
Medical applications
  • Congenital anomalies of the kidney and urinary tract (CAKUT)
  • Breathing disorders

Links