Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development

Krause, Ange; Zacharias, William J.; Camarata, Troy; Linkhart, Barbara; Law, Evelyn; Lischke, Antje; Miljan, Erik; Simon, Hans Georg

doi:10.1016/j.ydbio.2004.05.024

Cited by 76 publications

(116 citation statements)

References 73 publications

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“…By anchoring itself to the actin cytoskeleton through the N-terminal PDZ domain, ENH tethers Id2 to the cytoskeleton. This mechanism recapitulates that ascribed to other cytoskeleton-associated proteins for their ability to sequester transcription factors in the cytoplasm (28)(29)(30)(31)(32)(33). Although we have been focused primarily on the functional interaction between ENH and Id2 in neural cells, the ability of ENH to bind other Id proteins combined with its participation in differentiation of other tissue types (e.g., muscle) suggests that ENH may be a general inducer of differentiation through binding and cytoplasmic sequestration of Id proteins.…”

Section: Discussionsupporting

confidence: 66%

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The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Lasorella

Iavarone

2006

Proc. Natl. Acad. Sci. U.S.A.

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Id2 is a natural inhibitor of the basic helix-loop-helix transcription factors and the retinoblastoma tumor suppressor protein. Active Id2 prevents differentiation and promotes cell-cycle progression and tumorigenesis in the nervous system. A key event that regulates Id2 activity during differentiation is translocation from the nucleus to the cytoplasm. Here we show that the actin-associated protein enigma homolog (ENH) is a cytoplasmic retention factor for Id2. ENH contains three LIM domains, which bind to the helixloop-helix domain of Id proteins in vitro and in vivo. ENH is up-regulated during neural differentiation, and its ectopic expression in neuroblastoma cells leads to translocation of Id2 from the nucleus to the cytoplasm, with consequent inactivation of transcriptional and cell-cycle-promoting functions of Id2. Conversely, silencing of ENH by RNA interference prevents cytoplasmic relocation of Id2 in neuroblastoma cells differentiated with retinoic acid. Finally, the differentiated neural crest-derived tumor ganglioneuroblastoma coexpresses Id2 and ENH in the cytoplasm of ganglionic cells. These data indicate that ENH contributes to differentiation of the nervous system through cytoplasmic sequestration of Id2. They also suggest that ENH is a restraining factor of the oncogenic activity of Id proteins in neural tumors.differentiation ͉ enigma homolog ͉ Id proteins ͉ neural cancer I d2 is one of the four members of the Id protein family, a group of proteins known as inhibitor of differentiation (1, 2). Id2 lies at the center of a molecular network including the retinoblastoma (Rb) tumor suppressor protein and the basic helix-loop-helix (bHLH) transcription factors, the best-known targets for inhibition by Id2 (3, 4). These connections probably operate in a variety of cell types, but our work has characterized them in the nervous system (5-7). In this tissue, overexpression of Id proteins inhibits differentiation whereas ablation of Id genes induces premature differentiation of various neural cell types in vitro and in vivo (8-10). As physiologic regulator of Id2, Rb cooperates with bHLH transcription factors to promote cell-cycle arrest and differentiation in the developing brain. This pathway is subverted in tumor cells. Malignant transformation in the central and peripheral nervous system coincides with frequent elevation of Id2, a process typically implemented by the activation of oncoproteins such as Myc and Ews-Fli1 that up-regulate Id2 gene transcription, (6,7,11,12). The aberrant accumulation of Id2 contributes to uncontrolled proliferation and neoangiogenesis, two hallmarks of neural cancer (13).There is general agreement with the notion that differentiation of a variety of cell types requires elimination of Id function. However, the mechanisms by which the signaling pathways initiating differentiation in the nervous system inactivate Id proteins are unknown. Although Id are viewed mainly as nuclear proteins, recent papers reported that relocation of Id proteins to the cytoplasm is an effective...

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Section: Discussionsupporting

confidence: 66%

“…A common mechanism elicited in this process is sequestration of the factor into inactive compartments, usually through direct or indirect association with the cytoskeleton (28)(29)(30)(31)(32)(33). The cellular localization of Id2 was recently proposed to be critical for the regulation of Id2 function (10,14,15).…”

Section: Discussionmentioning

confidence: 99%

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Lasorella

Iavarone

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…The ventral mesoderm is where the rudimentary amphioxus heart tube forms, and the amphioxus orthologues of many other genes implicated in heart development in vertebrates, including Nk2-tinman and BMP2/4 (21,22), are expressed in this domain. Therefore, the first scenario is that the Tbx4/5 gene may have played an ancestral role in heart development and this function has been retained by the vertebrate Tbx5 and Tbx4 genes, since both are expressed in the heart anlagen and are required for heart development (23)(24)(25)(26). This implies that, during evolution of the Tbx4/5 subfamily, mutations occurred at the level of their cis-regulatory regions that account for the acquisition of a expression domain in LPM, where Tbx5 and Tbx4 can execute their limb-forming function.…”

Section: Discussionmentioning

confidence: 99%

Tbx4/5 gene duplication and the origin of vertebrate paired appendages

Minguillón

Gibson‐Brown

Logan

2009

Proc. Natl. Acad. Sci. U.S.A.

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Paired fins/limbs are one of the most successful vertebrate innovations, since they are used for numerous fundamental activities, including locomotion, feeding, and breeding. Gene duplication events generate new genes with the potential to acquire novel functions, and two rounds of genome duplication took place during vertebrate evolution. The cephalochordate amphioxus diverged from other chordates before these events and is widely used to deduce the functions of ancestral genes, present in single copy in amphioxus, compared to the functions of their duplicated vertebrate orthologues. The T-box genes Tbx5 and Tbx4 encode two closely related transcription factors that are the earliest factors required to initiate forelimb and hind limb outgrowth, respectively. Since the genetic components proposed to be responsible for acquiring a trait during evolution are likely to be involved in the formation of that same trait in living organisms, we investigated whether the duplication of an ancestral, single Tbx4/5 gene to give rise to distinct Tbx4 and Tbx5 genes has been instrumental in the acquisition of limbs during vertebrate evolution. We analyzed whether the amphioxus Tbx4/5 gene is able to initiate limb outgrowth, and assayed the amphioxus locus for the presence of limb-forming regulatory regions. We show that AmphiTbx4/5 is able to initiate limb outgrowth and, in contrast, that the genomic locus lacks the regulatory modules required for expression that would result in limb formation. We propose that changes at the level of Tbx5 and Tbx4 expression, rather than the generation of novel protein function, have been necessary for the acquisition of paired appendages during vertebrate evolution.S ince Ohno's visionary hypothesis concerning the origin of vertebrate innovations by genome duplication (1), numerous reports have been published supporting this concept (reviewed in ref.2). The cephalochordate amphioxus, a limbless extant invertebrate relative of the vertebrates (3), has been extensively used to study the ancestral functions of genes, present in single copy in amphioxus, that have been duplicated in the vertebrate lineage. Amphioxus exhibits many basal chordate characteristics, including the presence of a dorsal nerve cord, a notochord, and segmented paraxial mesoderm, but lacks many vertebrate characteristics such as migratory neural crest cells, a cranium, or an endoskeleton (4). We sought to investigate the origin of one of the most successful vertebrate innovations, paired appendages, which include the pectoral and pelvic fins of fish and their derived homologues, the forelimbs and hind limbs of tetrapods.The T-box genes Tbx4 and Tbx5 are paralogous genes that arose by duplication of a single, ancestral Tbx4/5 gene. Extant amphioxus possesses a single Tbx4/5 gene (AmphiTbx4/5) (5) and lacks paired appendages, whereas all jawed vertebrates with two pairs of paired appendages have distinct, postduplication Tbx4 and Tbx5 genes. In vertebrates, Tbx5 is expressed in the lateral plate mesoderm (LPM) of the presump...

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“…T-box transcription factors are involved in induction of mesendoderm (8), subdivision of posterior mesoderm into rostral and caudal domains, organ patterning and formation (9, 10), and body wall development (11). T-box genes can be rapidly induced by growth factors (12), function as transcriptional activators or repressors (13)(14)(15)(16)(17)(18)(19)(20), and interact with nucleosome assembly (21) or chromatin-modifying proteins (22).Coactivators and corepressors mediate the regulatory actions of SSTFs by a series of exchanged cofactor complexes that execute enzymatic modifications of nucleosomes and chromatin and interact with the basal transcription apparatus. Coactivators and corepressors are components of complexes that exhibit diverse enzymatic activities.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Pitx2-dependent Occupancy by Histone Deacetylases Is Associated with T-box Gene Regulation in Mammalian Abdominal Tissue

Hilton

Groß

Kioussi

2010

Journal of Biological Chemistry

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The homeodomain transcription factor Pitx2 and the T-box transcription factors are essential for organogenesis. Pitx2 and T-box genes are induced by growth factors and function as transcriptional activators or repressors. Gene expression analyses on abdominal tissue were used to identify seven of the T-box genes of the genome as Pitx2 target genes in the abdomen at embryonic day.10.5. Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression. As expected, activated genes showed reduced expression patterns, and repressed T-box genes showed increased expression patterns in the abdomen of Pitx2 mutants. Pitx2 occupied chromatin sites near all of these T-box genes. Co-occupancy by coactivators, corepressors, and histone acetylation at these sites was frequently Pitx2-dependent. Genes repressed by Pitx2 generally showed increased histone acetylation and decreased histone deacetylase (HDAC)/corepressor occupancy in Pitx2 mutants. The lower N-CoR, HDAC1, and HDAC3 occupancy observed at multiple sites along Tbx1 chromatin in mutants is consistent with the model that increased histone acetylation and gene expression of Tbx1 may result from a loss of recruitment of corepressors by Pitx2. Genes activated by Pitx2 showed less consistent patterns in chromatin analyses. Reduced H4 acetylation and increased HDAC1/nuclear receptor corepressor (N-CoR) occupancy at some Tbx4 sites were accompanied by increased H3 acetylation and reduced HDAC3 occupancy at the same or other more distal chromatin sites in mutants. Pitx2-dependent occupancy by corepressors resulted in alteration of the acetylation levels of several T-box genes, whereas Pitx2-dependent occupancy by coactivators was more site-localized. These studies will provide the basic scientific underpinning to understand abdominal wall syndromes.Definitive endoderm and lateral plate mesoderm cells are formed and begin to migrate laterally between the ectoderm and primitive endoderm during early gastrulation. Together, these cells form the abdominal wall that begins to enclose the internal organs shortly after the mouse embryo turns. The abdominal wall at mouse embryonic day (E) 3 9.5 is composed of lateral plate mesoderm-derived mesenchymal cells inserted between ectoderm-and endoderm-derived cell layers. Abdominal somites are beginning to extend ventrally into the lateral plate-derived mesenchyme to form abdominal wall muscle anlagen. Classic ventral body wall defects are characterized by a thin body wall, muscular dysplasia, and/or absence of midline fusion (1, 2).Several sequence-specific DNA binding transcription factors (SSTFs) are involved in the pathogenesis of congenital body wall defects. These include the homeodomain transcription factor Pitx2, which is essential for organ formation and body wall closure (3-6). Pitx2 is a target of growth factor signaling pathways that mediate cell type-specific control of proliferation. Activation of the Wnt/␤-catenin pathway results in the release of Pitx2-associated corepressors and mediates recruitmen...

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Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development

Cited by 76 publications

References 73 publications

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

The protein ENH is a cytoplasmic sequestration factor for Id2 in normal and tumor cells from the nervous system

Tbx4/5 gene duplication and the origin of vertebrate paired appendages

Pitx2-dependent Occupancy by Histone Deacetylases Is Associated with T-box Gene Regulation in Mammalian Abdominal Tissue

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