The Stomach Mesenchymal Transcription Factor Barx1 Specifies Gastric Epithelial Identity through Inhibition of Transient Wnt Signaling

Kim, Byeong–Moo; Buchner, Georg; Milétich, Isabelle; Sharpe, Paul T.; Shivdasani, Ramesh A.

doi:10.1016/j.devcel.2005.01.015

Cited by 185 publications

(266 citation statements)

References 50 publications

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“…To analyze the role of Barx1 in molar tooth development, we generated mutant mice using gene targeting (Fig. S1) (13). Mutants die at birth most likely from cleft palate.…”

Section: Resultsmentioning

confidence: 99%

Developmental stalling and organ-autonomous regulation of morphogenesis

Milétich

Zhang

et al. 2011

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

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Timing of organ development during embryogenesis is coordinated such that at birth, organ and fetal size and maturity are appropriately proportioned. The extent to which local developmental timers are integrated with each other and with the signaling interactions that regulate morphogenesis to achieve this end is not understood. Using the absolute requirement for a signaling pathway activity (bone morphogenetic protein, BMP) during a critical stage of tooth development, we show that suboptimal levels of BMP signaling do not lead to abnormal morphogenesis, as suggested by mutants affecting BMP signaling, but to a 24-h stalling of the intrinsic developmental clock of the tooth. During this time, BMP levels accumulate to reach critical levels whereupon tooth development restarts, accelerates to catch up with development of the rest of the embryo and completes normal morphogenesis. This suggests that individual organs can autonomously control their developmental timing to adjust their stage of development to that of other organs. We also find that although BMP signaling is critical for the bud-to-cap transition in all teeth, levels of BMP signaling are regulated differently in multicusped teeth. We identify an interaction between two homeodomain transcription factors, Barx1 and Msx1, which is responsible for setting critical levels of BMP activity in multicusped teeth and provides evidence that correlates the levels of Barx1 transcriptional activity with cuspal complexity. This study highlights the importance of absolute levels of signaling activity for development and illustrates remarkable self-regulation in organogenesis that ensures coordination of developmental processes such that timing is subordinate to developmental structure.

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“…To analyze the role of Barx1 in molar tooth development, we generated mutant mice using gene targeting (Fig. S1) (13). Mutants die at birth most likely from cleft palate.…”

Section: Resultsmentioning

confidence: 99%

Developmental stalling and organ-autonomous regulation of morphogenesis

Milétich

Zhang

et al. 2011

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

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“…Considering that the expression of the homeobox genes, such as BARX1 and PITX1, is confined to the stomach mesenchyme during g astrointestinal development [23] , we studied PITX1 expression in human gastric cancer tissues. In our study, PITX1 expression declined in 63.3% cases of gastric cancer, compared with adjacent normal tissues (P < 0.001).…”

Section: Discussionmentioning

confidence: 99%

Expression of pituitary homeobox 1 gene in human gastric carcinogenesis and its clinicopathological significance

Chen¹,

Chen²,

Yang³

et al. 2008

WJG

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AIM:To investigate the effect of pituitary homeobox 1 (PITX1) expression in cases of human gastric cancer on cancer differentiation and progression, and carcinogenesis. METHODS:Using polyclonal PITX1 antibodies, we studied the expression of PITX1 in normal gastric mucosa, atypical hyperplasia, intestinal metaplasia, and cancer tissue samples from 83 gastric cancer patients by immunohistochemistry. Moreover, semi-reverse transcription polymerase chain reaction (semi-RT-PCR) was performed to detect the mRNA level of PITX1 in three gastric cancer cell lines and a normal gastric epithelial cell line. Subsequently, somatic mutations of the PITX1 gene in 71 gastric cancer patients were analyzed by a combination of denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. RESULTS:Immunohistochemistry showed that PITX1 was strongly or moderately expressed in the parietal cells of normal gastric mucosa (100%), while 55 (66.3%) out of 83 samples of gastric cancers showed decreased PITX1 expression. Moreover, PITX1 expression was reduced in 20 out of 28 cases (71.5%) of intestinal metaplasia, but in only 1 out of 9 cases (11%) of atypical hyperplasia. More importantly, PITX1 expression was significantly associated with the differentiation, position and invasion depth of gastric cancers (r = -0.316, P < 0.01; r = 0.213, P < 0.05; r = -0.259, P < 0.05, respectively). Similarly, levels of PITX1 mRNA were significantly decreased in 2 gastric cancer cell lines, BGC-823 and SGC-7901, compared with the normal gastric epithelial cell line GES-1 (0.306 ± 0.060 vs 0.722 ± 0.102, P < 0.05; 0.356 ± 0.081 vs 0.722 ± 0.102, P < 0.05, respectively). Nevertheless, no somatic mutation of PITX1 gene was found in 71 samples of gastric cancer by DHPLC analysis followed by sequencing.CONCLUSION: Down-regulation of PITX1 may be a frequent molecular event in gastric carcinogenesis. Aberrant levels of PITX1 expression may be closely correlated with the progression and differentiation of gastric cancer.

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“…The restricted Barx1 expression in the presumptive molar mesenchyme is the result of the antagonistic effects of Fgf8 and Bmp4, which leads to the tooth type determination of the molar (Tucker et al, 1998). Although Barx1 knockout mice were recently generated, a tooth phenotype has not yet been reported (Kim et al, 2005). .…”

Section: Barx1 Is Critical For Molar Tooth Development Beyond the Budmentioning

confidence: 99%

Application of lentivirus‐mediated RNAi in studying gene function in mammalian tooth development

Song

Zhang

et al. 2006

Developmental Dynamics

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RNA interference (RNAi) has recently become a powerful tool to silence gene expression in mammalian cells, but its application in assessing gene function in mammalian developing organs remains highly limited. Here we describe several unique developmental properties of the mouse molar germ. Embryonic molar mesenchyme, but not the incisor mesenchyme, once dissociated into single cell suspension and re-aggregated, retains its odontogenic potential, the capability of a tissue to instruct an adjacent tissue to initiate tooth formation. Dissociated molar mesenchymal cells, even after being plated in cell culture, retain odontogenic competence, the capability of a tissue to respond to odontogenic signals and to support tooth formation. Most interestingly, while dissociated epithelial and mesenchymal cells of molar tooth germ are mixed and re-aggregated, the epithelial cells are able to sort out from the mesenchymal cells and organize into a well-defined dental epithelial structure, leading to the formation of a well-differentiated tooth organ after sub-renal culture. These unique molar developmental properties allow us to develop a strategy using a lentivirus-mediated RNAi approach to silence gene expression in dental mesenchymal cells and assess gene function in tooth development. We show that knockdown of Msx1 or Dlx2 expression in the dental mesenchyme faithfully recapitulates the tooth phenotype of their targeted mutant mice. Silencing of Barx1 expression in the dental mesenchyme causes an arrest of tooth development at the bud stage, demonstrating a crucial role for Barx1 in tooth formation. Our studies have established a reliable and rapid assay that would permit large-scale analysis of gene function in mammalian tooth development.

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The Stomach Mesenchymal Transcription Factor Barx1 Specifies Gastric Epithelial Identity through Inhibition of Transient Wnt Signaling

Cited by 185 publications

References 50 publications

Developmental stalling and organ-autonomous regulation of morphogenesis

Developmental stalling and organ-autonomous regulation of morphogenesis

Expression of pituitary homeobox 1 gene in human gastric carcinogenesis and its clinicopathological significance

Application of lentivirus‐mediated RNAi in studying gene function in mammalian tooth development

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