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.
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.
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).
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).
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.
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).
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).
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.
September 26th, 2016
TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.
February 21st, 2013
The tiptop/teashirt genes regulate cell differentiation and renal physiology in Drosophila.
July 14th, 2010
Teashirt 3 regulates development of neurons involved in both respiratory rhythm and airflow control.
October 1st, 2008
Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4.
July 15th, 2005
A critical role of teashirt for patterning the ventral epidermis is masked by ectopic expression of tiptop, a paralog of teashirt in Drosophila.
May 23rd, 2005
Expression patterns of the three Teashirt-related genes define specific boundaries in the developing and postnatal mouse forebrain.
March 1st, 2004
Three putative murine Teashirt orthologues specify trunk structures in Drosophila in the same way as the Drosophila teashirt gene.
March 1st, 2000
Vertebrate orthologues of the Drosophila region-specific patterning gene teashirt.
January 11th, 1991
The gene teashirt is required for the development of Drosophila embryonic trunk segments and encodes a protein with widely spaced zinc finger motifs.
May 6th, 2013
TSHZ3 and SOX9 Regulate the Timing of Smooth Muscle Cell Differentiation in the Ureter by Reducing Myocardin Activity.
August 1st, 2012
Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes.
March 23rd, 2012
Teashirt in cell proliferation
January 1st, 2012
Toward a new role for plasma membrane sodium-dependent glutamate transporters of astrocytes: maintenance of antioxidant defenses beyond extracellular glutamate clearance.
January 1st, 2012
Maintenance of antioxidant defenses of brain cells: plasma membrane glutamate transporters and beyond.
July 14th, 2011
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.
July 1st, 2011
Teashirt-3, a novel regulator of muscle differentiation, associates with BRG1-associated factor 57 (BAF57) to inhibit myogenin gene expression.
January 1st, 2010
Ureter myogenesis: putting Teashirt into context.
January 1st, 2010
Analysis of TSHZ2 and TSHZ3 genes in congenital pelvi-ureteric junction obstruction.
August 15th, 2007
Tshz1 is required for axial skeleton, soft palate and middle ear development in mice.
July 1st, 2007
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.
October 1st, 2006
Teashirt 3 expression in the chick embryo reveals a remarkable association with tendon development.
August 8th, 2006
Chaetognath phylogenomics: a protostome with deuterostome-like development.
July 1st, 2005
Restricted expression of a median Hox gene in the central nervous system of chaetognaths.
April 1st, 2003
Hox gene survey in the chaetognath Spadella cephaloptera: evolutionary implications.
June 12th, 2002
Characterisation of set-1, a conserved PR/SET domain gene in Caenorhabditis elegans.
March 1st, 2002
Grunge, related to human Atrophin-like proteins, has multiple functions in Drosophila development.
January 1st, 2002
Cubitus interruptus acts to specify naked cuticle in the trunk of Drosophila embryos.
January 1st, 2000
Characterization of the two zebrafish orthologues of the KAL-1 gene underlying X chromosome-linked Kallmann syndrome.
November 15th, 1999
The role of Teashirt in proximal leg development in Drosophila: ectopic Teashirt expression reveals different cell behaviours in ventral and dorsal domains.
November 1st, 1999
The levels of the bancal product, a Drosophila homologue of vertebrate hnRNP K protein, affect cell proliferation and apoptosis in imaginal disc cells.
April 15th, 1999
The C-terminal domain of armadillo binds to hypophosphorylated teashirt to modulate wingless signalling in Drosophila.
July 30th, 1998
Trunk-specific modulation of wingless signalling in Drosophila by teashirt binding to armadillo.
November 1st, 1997
Transcriptional regulation of the Drosophila homeotic gene teashirt by the homeodomain protein Fushi tarazu.
January 1st, 1997
GIF-DB, a WWW database on gene interactions involved in Drosophila melanogaster development.
October 10th, 1996
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.
October 1st, 1988