The Pitx2 protein in mouse development

Hjalt, Tord; Semina, Elena V.; Amendt, Brad A.; Murray, Jeffrey C.

doi:10.1002/(sici)1097-0177(200005)218:1<195::aid-dvdy17>3.0.co;2-c

Cited by 121 publications

(67 citation statements)

References 23 publications

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“…Consistent with these observations it has been shown that the ANF gene is regulated by cardiac muscle-specific transcription factors (22,23). ANF and Pitx2 are expressed in overlapping domains and developmental stages during heart morphogenesis (24,25). A general theme in developmental biology is the use of a combinatorial code of transcription factors to control gene expression.…”

mentioning

confidence: 65%

“…We have previously shown Pitx2 protein expression in the developing mouse heart. At E9.5 Pitx2 is expressed in the wall of the left atrium, at E11.5 it is seen in the septum primum, and at E12.5 in the left atrium, septum primum, and wall of the right atrium (25). Interestingly, ANF transcripts have been detected in these same regions and at identical stages of mouse development (24).…”

Section: Discussionmentioning

confidence: 97%

“…Approximately, 200 ng of purified PITX2 proteins and 20 g of cell lysates were analyzed by Western blots. Following SDS gel electrophoresis, the proteins were transferred to polyvinylidene difluoride filters (Millipore), immunoblotted, and detected using PITX2 antibody P2R10 (25,33) and ECL reagents from Amersham Biosciences.…”

Section: Expression and Purification Of Gst-pitx2 Fusionmentioning

confidence: 99%

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PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

Ganga

Espinoza

Cox

et al. 2003

Journal of Biological Chemistry

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PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2؊/؊ mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor (ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.

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confidence: 65%

Section: Discussionmentioning

confidence: 97%

Section: Expression and Purification Of Gst-pitx2 Fusionmentioning

confidence: 99%

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PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

Ganga

Espinoza

Cox

et al. 2003

Journal of Biological Chemistry

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“…What about in the oral epithelium? In the oral epithelium it is clear that PITX2 is expressed early and plays an important role in tooth development (42)(43)(44). However, the expression and function of MEF2 expression in the epithelium is not clear.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A

Toro¹,

Saadi²,

Kuburas

et al. 2004

Journal of Biological Chemistry

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The PITX2 homeodomain protein is mutated in patients with Axenfeld-Rieger syndrome and is involved in the development of multiple organ systems, including the heart. We have examined the interaction of PITX2 isoforms with myocyte-enhancing factor 2A (MEF2A), which is a known regulator of cardiac development. A direct interaction between PITX2a and MEF2A was demonstrated using yeast two-hybrid and GST pulldown assays. To study the functional significance of this interaction, we used the atrial natriuretic factor (ANF) promoter. Coexpression of MEF2A and PITX2a or Pitx2c resulted in a strong synergistic activation of the ANF promoter in LS8 oral epithelial cells but not in other cell lines (NIH/3T3, Chinese hamster ovary, or C2C12). The synergism was dependent on promoter context, because it required MEF2 binding sites and was not seen with two other PITX2 target promoters. DNA binding by MEF2A was required but not sufficient for synergism. Upstream activators of p38 MAP kinases, MKK3 and MKK6, increased PITX2a and Pitx2c activity to yield up to 90-fold activation of the ANF promoter in LS8 cells. Because Axenfeld-Rieger syndrome is autosomal dominant and affects development of the oral epithelium, we tested one of the known PITX2 mutants. The PITX2a-K88E mutant protein suppressed wild type PITX2a synergism with MEF2A. These results demonstrate a promoter-and cell-specific functional interaction between PITX2 and MEF2A and suggest the possibility of coordinate control by these factors in the oral epithelium.The PITX2 gene was cloned based on its linkage in AxenfeldRieger syndrome (ARS) 1 (1). ARS is an autosomal dominant human disorder characterized by ocular anterior chamber anomalies causing glaucoma in Ͼ50% of affected individuals as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities (1-3). Other features associated with this syndrome include abnormal cardiac, limb, and pituitary development. PITX2 is a member of the bicoid/paired-like homeodomain family (3, 4). There are three isoforms, PITX2a, b, c, that differ only in their amino-terminal regions. The Pitx2 knock-out mouse is lethal at embryonic day 15 because of cardiac abnormalities and shows defects in cardiac positioning, atrial septation, and outflow tract development (4). Pitx2 is a proliferation target in the Wnt/Dvl pathway, which, when disrupted, leads to cardiac outflow tract abnormalities (5). Pitx2 has also been shown to be a downstream target in left-right asymmetry pathways and organogenesis (6 -9). It is expressed asymmetrically on the left side of the lateral plate mesoderm and derivative organs, including the heart and the gut.We have used the yeast two-hybrid assay to analyze candidate PITX2 interacting partners. With respect to the role of PITX2 in heart development, we were intrigued by the recent findings that PITX2 could activate the promoter of the atrial natriuretic factor (ANF) gene (10). ANF plays a key role in electrolyte and fluid homeostasis in the cardiovascular system by causing natriure...

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“…Pitx2 is the earliest transcription marker observed in tooth development and is specifically restricted to the developing dental epithelium (24,39). In tooth formation, as in all organs, developmental programs are usually initiated by more than one gene and cell type acting in concert to promote cell proliferation, migration, and/or differentiation.…”

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confidence: 99%

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

Amen

Liu

Vadlamudi

et al. 2007

Molecular and Cellular Biology

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105

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Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with ␤-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and ␤-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length ␤-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated ␤-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and ␤-catenin in which the Lef-1 ␤-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, ␤-catenin interacts with the PITX2 homeodomain and Lef-1 interacts with the PITX2 C-terminal tail. Lef-1 and ␤-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and ␤-catenin.Pitx2 and Lef-1 encode two transcription factors whose expression can be regulated by early signaling events involved in numerous developmental programs. Pitx2 and Lef-1 are differentially expressed in many tissues, and they demonstrate overlapping expression during tooth development. Lef-1 can be activated by BMP, Wnt, Smads, and transforming growth factor ␤ signaling (18,32,33). Furthermore, Lef-1 transcriptional activity is regulated by its interaction with ␤-catenin. Secreted

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The Pitx2 protein in mouse development

Cited by 121 publications

References 23 publications

PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression

Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

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