Isolation and Developmental Expression Analysis of Tbx22, the Mouse Homolog of the Human X-linked Cleft Palate Gene

Department of Biology, University of Rochester, Rochester, New York 14642, USA.
Developmental Dynamics (Impact Factor: 2.38). 11/2002; 225(3):322-6. DOI: 10.1002/dvdy.10154
Source: PubMed


Mutations in the TBX22 gene have been identified recently in patients with the X-linked cleft palate and ankyloglossia syndrome, suggesting that the TBX22 transcription factor plays an important role in palate development. However, because ankyloglossia has been reported in the majority of patients with TBX22 mutations, it has been speculated that the cleft palate phenotype is secondary to defective fetal tongue movement. To understand the role of TBX22 in disease pathogenesis and in normal development, it is necessary to carry out a detailed temporal and spatial gene expression analysis. We report here the isolation and developmental expression analysis of the mouse homolog Tbx22. The mouse Tbx22 gene encodes a putative protein of 517 amino acid residues, which shares 72% overall amino acid sequence identity with the human TBX22 protein. By using interspecific backcross analysis, we have localized the Tbx22 gene to mouse chromosome X, in a region syntenic to human chromosome Xq21, where the TBX22 gene resides, indicating that Tbx22 is the ortholog of human TBX22. Our in situ hybridization analysis shows that Tbx22 is expressed in a temporally and spatially highly restricted pattern during mouse palate and tongue development. Together with the mutant phenotypes in human patients, our data indicate a primary role for Tbx22 in both palate and tongue development.

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Available from: Rulang Jiang, Jan 06, 2015
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    • "Tbx2 function is required for formation of the intersomitic blood vessels (Harrelson and Papaioannou, 2006), and therefore does not contribute to the patterning of the vertebral column or ribs. Similarly, Tbx22 null embryos do not exhibit vertebral or rib defects, but rather display a cleft-palate phenotype (Bush et al., 2002). Strikingly, the observed phenotypes of 3-component embryos resembled those of Tbx15 and Tbx18 null embryos. "
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    ABSTRACT: Members of the T-box family of transcription factors play essential roles in cell type specification, differentiation, and proliferation during embryonic development. All T-box family members share a common DNA binding domain - the T-domain - and can therefore recognize similar sequences. Consequently, T-box proteins that are co-expressed during development have the potential to compete for binding at downstream targets. In the mouse, Tbx6 is expressed in the primitive streak and presomitic mesoderm, and is sharply down-regulated upon segmentation of the paraxial mesoderm. We sought to determine the phenotypic and molecular consequences of ectopically expressing Tbx6 within the segmented paraxial mesoderm and its derivatives using a 3-component transgenic system. The vertebral column, ribs, and appendicular skeleton were all affected in these embryos, which resembled Tbx18 and Tbx15 null embryos. We hypothesize that these phenotypes result from competition between the ectopically expressed Tbx6 and the endogenously expressed Tbx18 and Tbx15 at the binding sites of target genes. In vitro luciferase transcriptional assays provide further support for this hypothesis.
    Preview · Article · Nov 2010 · Developmental Biology
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    • "These mouse and human studies do not reveal functions of Tbx22 in the frontonasal mass possibly due to functional redundancy with other Tbox genes also expressed in this region (Chapman et al., 1996; Kraus et al., 2001; Singh et al., 2005; Farin et al., 2007; Zirzow et al., 2009). In addition, Tbx22 has a rather late onset of expression in mouse, first appearing between E9.5 (Farin et al., 2008) and E10.5 (Bush et al., 2002). Thus, the main aspects of neural crest and frontonasal mass patterning would have taken place prior to the onset of Tbx22 expression. "
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    ABSTRACT: The frontonasal mass gives rise to the facial midline and fuses with the maxillary prominence to form the upper lip. Here we focus on the regulation and function of TBX22, a repressor dynamically expressed in the frontonasal mass. Both FGF and Noggin (a BMP antagonist) strongly induce gTBX22, however, each has opposite effects on morphogenesis - Noggin inhibits whereas FGF stimulates growth. To determine whether TBX22 mediates these effects, we used retroviruses to locally increase expression levels. RCAS::hTBX22 decreased proliferation, reduced expression of MSX2 and DLX5 and caused cleft lip. Decreased levels of endogenous gTBX22 were also observed but were not the primary cause of the phenotype as determined in rescue experiments. Our data suggest that genetic or environmental insults such as those affecting the BMP pathway could lead to a gain-of-function of TBX22 and predispose an individual to cleft lip.
    Full-text · Article · Feb 2010 · Developmental Dynamics
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    • "Additionally, haploinsufficiency of the TBX1 gene is the major gene responsible for DiGeorge syndrome, where one of the features is CP (DGS; MIM188400). Expression of Tbx22 in mouse and chicken is seen in the posterior palate, caudal tongue, nasal mesenchyme, extra-ocular mesenchyme (Supplementary Material, Fig. S1) and early somites (12,18,19). This pattern correlates well with the phenotypic characteristics found in CPX patients but suggests additional roles for TBX22 in development. "
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    ABSTRACT: Craniofacial defects involving the lip and/or palate are among the most common human birth defects. X-linked cleft palate and ankyloglossia results from loss-of-function mutations in the gene encoding the T-box transcription factor TBX22. Further studies show that TBX22 mutations are also found in around 5% of non-syndromic cleft palate patients. Although palate defects are obvious at birth, the underlying developmental pathogenesis remains unclear. Here, we report a Tbx22(null) mouse, which has a submucous cleft palate (SMCP) and ankyloglossia, similar to the human phenotype, with a small minority showing overt clefts. We also find persistent oro-nasal membranes or, in some mice a partial rupture, resulting in choanal atresia. Each of these defects can cause severe breathing and/or feeding difficulties in the newborn pups, which results in approximately 50% post-natal lethality. Analysis of the craniofacial skeleton demonstrates a marked reduction in bone formation in the posterior hard palate, resulting in the classic notch associated with SMCP. Our results suggest that Tbx22 plays an important role in the osteogenic patterning of the posterior hard palate. Ossification is severely reduced after condensation of the palatal mesenchyme, resulting from a delay in the maturation of osteoblasts. Rather than having a major role in palatal shelf closure, we show that Tbx22 is an important determinant for intramembranous bone formation in the posterior hard palate, which underpins normal palate development and function. These findings could have important implications for the molecular diagnosis in patients with isolated SMCP and/or unexplained choanal atresia.
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