TEAM

Transcriptional regulatory networks in development and diseases

Group leader : L. Fasano

Presentation
Publications

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.

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).

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”).

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.

Selected publications

PUBLICATION

March 15th, 2022

Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

Caubit X, Gubellini P, Roubertoux PL, Carlier M, Molitor J, Chabbert D, Metwaly M, Salin P, Fatmi A, Belaidouni Y, Brosse L, Kerkerian-Le Goff L, Fasano L.

Transl Psychiatry. 2022 Mar 15;12(1):106. doi: 10.1038/s41398-022-01865-6. PMID: 35292625

Transcriptional regulatory networks in development and diseases

Group leader : L. Fasano

FOR BEGINNERS

FOR SPECIALISTS

Selected publications

Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

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

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

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

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

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

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

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

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

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

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

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

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

Teashirt in cell proliferation

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

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

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.

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

Ureter myogenesis: putting Teashirt into context.

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

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

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.

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

Chaetognath phylogenomics: a protostome with deuterostome-like development.

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

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

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

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

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

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

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

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

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

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

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

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

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.

Monitoring positional information during oogenesis in adult Drosophila.

Research

Keywords

Interactions

IBDM

INTERNATIONAL

Funding

Members more

Laurent Fasano

Zakaria Blaine

morgane Bonnafoux

Pierre Lienart

Elise Arbeille

Xavier Caubit

Ahmed Fatmi

Laurence Had

Alumni

Overview

Animal model organism

Biological process studied

Biological techniques

Medical applications

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