TSHZ3 and SOX9 regulate the timing of smooth muscle cell differentiation in the ureter by reducing myocardin activity

International audienceSmooth muscle cells are of key importance for the proper functioning of different visceral organs including those of the urogenital system. In the mouse ureter, the two transcriptional regulators TSHZ3 and SOX9 are independently required for initiation of smooth muscle differentiation from uncommitted mesenchymal precursor cells. However, it has remained unclear whether TSHZ3 and SOX9 act independently or as part of a larger regulatory network. Here, we set out to characterize the molecular function of TSHZ3 in the differentiation of the ureteric mesenchyme. Using a yeast-two-hybrid screen, we identified SOX9 as an interacting protein. We show that TSHZ3 also binds to the master regulator of the smooth muscle program, MYOCD, and displaces it from the coregulator SRF, thereby disrupting the activation of smooth muscle specific genes. We found that the initiation of the expression of smooth muscle specific genes in MYOCD-positive ureteric mesenchyme coincides with the down regulation of Sox9 expression, identifying SOX9 as a possible negative regulator of smooth muscle cell differentiation. To test this hypothesis, we prolonged the expression of Sox9 in the ureteric mesenchyme in vivo. We found that Sox9 does not affect Myocd expression but significantly reduces the expression of MYOCD/SRF-dependent smooth muscle genes, suggesting that down-regulation of Sox9 is a prerequisite for MYOCD activity. We propose that the dynamic expression of Sox9 and the interaction between TSHZ3, SOX9 and MYOCD provide a mechanism that regulates the pace of progression of the myogenic program in the ureter

Chætognath transcriptome reveals ancestral and unique features among bilaterians

The chætognath transcriptome reveals unusual genomic features in the evolution of this protostome and suggests that it could be used as a model organism for bilaterians

Construct Validity and Cross Validity of a Test Battery Modeling Autism Spectrum Disorder (ASD) in Mice

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Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder–like Behavior

International audienceBACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3 flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, w50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic syn-apse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency

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

Drosophila teashirt (tsh) is involved in the patterning of the trunk identity together with the Hox genes. In addition, it is also a player in the Wingless and the Hedgehog pathways. In birds and mammals, three Tshz genes are identified and the expression patterns for mouse Tshz1 and Tshz2 have been reported during embryogenesis. Recently, we showed that all three mouse Tshz genes can rescue the Drosophila tsh loss-of-function phenotype, indicating that the function of the teashirt genes has been conserved during evolution. Here we describe the expression pattern of chick TSHZ3 during embryogenesis. Chick TSHZ3 is expressed in several tissues including mesodermal derivatives, the central and peripheral nervous systems. Emphasis is laid on the dynamic expression occurring in regions of the somites and limbs where tendons develop. We show that TSHZ3 is activated in the somites by FGF8, a known inducer of the tendon marker SCX. (c) 2006 Elsevier B.V. All rights reserved

Tshz3 a marker of Satellite cells (study of his role in the regulation of mouse myogenesis)

L unité cellulaire du muscle squelettique est la myofibre, un syncytium hautement spécialisé générant la contraction musculaire. Au cours de la croissance et de la régénération musculaire, les cellules satellites quiescentes (cellules souches) du muscle squelettique adulte sont activées, prolifèrent puis fusionnent formant de nouvelles fibres. A l aide d un modèle murin de régénération et de cultures primaires, j ai identifié TSHZ3 comme un nouveau marqueur des cellules satellites quiescentes et activées. Dans la lignée cellulaire C2C12, j ai mis en évidence un effet répresseur spécifique de Tshz3 sur la différenciation myogénique. L entrée des myoblastes dans la voie de différenciation terminale est déclenchée par le facteur Myogenin (MYOG). L activation de la transcription du gène myogenin (Myog) est dépendante du facteur MYOD et fait intervenir le complexe de remodelage de la chromatine SWI/SNF. In vitro, TSHZ3 interagit avec BAF57 une sous unité du complexe SWI/SNF. TSHZ3 réprime l activation dépendante de MYOD sur le promoteur proximal de Myog et cette répression dépend en partie de la présence de BAF57. L activité répressive et la cinétique d expression de Tshz3, indique que TSHZ3 pourrait empêcher l activation prématurée du promoteur Myog lors de la prolifération des cellules satellites activées. TSHZ3 pourrait ainsi participer aux mécanismes de régulation permettant de contrôler l équilibre entre prolifération, différenciation et renouvellement des progéniteurs myogéniques.Skeletal muscles are made of several units called myofibers, a syncitium into which muscular contraction is generated. During the muscle growth and repair, the quiescent Satellite Cells (SCs; adult stem cells) become activated, proliferate and differentiate to form new multinucleated myofibers. In animal model and primary culture, I found that, Tshz3 was strongly expressed in the quiescent and activated satellite cells.In C2C12 myoblast cells, I showed a specific repressive effect of TSHZ3 on the myogenic differentiation. The terminal differentiation of the myoblastes is trigger by Myogenin (Myog). The transcriptional activation of Myog promoter involves MYOD and the SWI/SNF remodelling complex. In vitro, I showed that TSHZ3 interacts with BAF57, a subunit of the SWI/SNF complex. TSHZ3 represses the MYOD-dependant activation on the Myog promoter. This specific repression involves in part BAF57.The repressive activity of and the temporal dynamic of expression of Tshz3, indicated that TSHZ3 potentially is required to impede the premature activation of the Myog promotor during the SCs proliferation. These results suggest that TSHZ3 plays important roles in the molecular mechanisms operating in activated SCs when there are poised between proliferation, differentiation and self renewal of muscular progenitors.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

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

Hox genes encode a set of evolutionarily conserved transcription factors that regulate anterior-posterior patterning. Here we report the first developmental expression of a Hox gene from Chaetognatha. These metazoans have been shown recently to be part of the protostome group of bilaterians. We describe the analysis of the SceMed4 gene (a Spadella cephaloptera Median Hox gene) including its expression from late stages of egg development to 7 days after hatching. In all of these stages, SceMed4 is expressed in two lateral stripes in a restricted region of the developing ventral ganglion

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

International audienceThe physiological activities of organs are underpinned by an interplay between the distinct cell types they contain. However, little is known about the genetic control of patterned cell differentiation during organ development. We show that the conserved Teashirt transcription factors are decisive for the differentiation of a subset of secretory cells, stellate cells, in Drosophila melanogaster renal tubules. Teashirt controls the expression of the water channel Drip, the chloride conductance channel CLC-a and the Leukokinin receptor (LKR), all of which characterise differentiated stellate cells and are required for primary urine production and responsiveness to diuretic stimuli. Teashirt also controls a dramatic transformation in cell morphology, from cuboidal to the eponymous stellate shape, during metamorphosis. teashirt interacts with cut, which encodes a transcription factor that underlies the differentiation of the primary, principal secretory cells, establishing a reciprocal negative-feedback loop that ensures the full differentiation of both cell types. Loss of teashirt leads to ineffective urine production, failure of homeostasis and premature lethality. Stellate cell-specific expression of the teashirt paralogue tiptop, which is not normally expressed in larval or adult stellate cells, almost completely rescues teashirt loss of expression from stellate cells. We demonstrate conservation in the expression of the family of tiptop/teashirt genes in lower insects and establish conservation in the targets of Teashirt transcription factors in mouse embryonic kidney

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

Members of the Tshz gene family encode putative zinc fingers transcription factors that are broadly expressed during mouse embryogenesis. Tshz1 is detected from E9.5 in the somites, the spinal cord, the limb buds and the branchial arches. In order to assess the function of Tshz1 during mouse development, we generated Tshz1-deficient mice. Tshz1 inactivation leads to neonatal lethality and causes multiple developmental defects. In the craniofacial region, loss of Tshz1 function leads to specific malformations of middle ear components, including the malleus and the tympanic ring. Tshz1(-/-) mice exhibited Hox-like vertebral malformations and homeotic transformations in the cervical and thoracic regions, suggesting that Tshz1 and Hox genes are involved in common pathways to control skeletal morphogenesis. Finally, we demonstrate that Tshz1 is required for the development of the soft palate

Vertebrate orthologues of the Drosophila region-specific patterning gene teashirt

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