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B-Catenin Deficiency Causes Digeorge Syndrome-Like Phenotypes Through Regulation of Tbx1 Sung-Ho Huh and David M

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B-Catenin Deficiency Causes Digeorge Syndrome-Like Phenotypes Through Regulation of Tbx1 Sung-Ho Huh and David M RESEARCH ARTICLE 1137 Development 137, 1137-1147 (2010) doi:10.1242/dev.045534 © 2010. Published by The Company of Biologists Ltd b-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1 Sung-Ho Huh and David M. Ornitz* SUMMARY DiGeorge syndrome (DGS) is a common genetic disease characterized by pharyngeal apparatus malformations and defects in cardiovascular, craniofacial and glandular development. TBX1 is the most likely candidate disease-causing gene and is located within a 22q11.2 chromosomal deletion that is associated with most cases of DGS. Here, we show that canonical Wnt–b-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of b-catenin (Ctnnb1) in mice caused abnormalities within the DGS phenotypic spectrum, including great vessel malformations, hypoplastic pulmonary and aortic arch arteries, cardiac malformations, micrognathia, thymus hypoplasia and mislocalization of the parathyroid gland. In a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt–b-catenin signaling caused an increased incidence and severity of DGS- like phenotypes. Additionally, reducing the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1. These findings identify Wnt–b-catenin signaling as a crucial upstream regulator of a Tbx1–Fgf8 signaling pathway and suggest that factors that affect Wnt–b-catenin signaling could modify the incidence and severity of DGS. KEY WORDS: b-catenin, Tbx1, Fgf8, Pharyngeal arch, DiGeorge syndrome INTRODUCTION is expressed in the pharyngeal arch endoderm, core mesoderm, DiGeorge syndrome (DGS) is one of the most common genetic anterior heart field and head mesenchyme, but is absent in neural disorders with an incidence of 1 in 4000 live births. More than 90% crest-derived mesenchyme (Chapman et al., 1996; Torres-Juan et al., of DGS cases are associated with hemizygous deletion of 2007; Vitelli et al., 2002a). chromosome 22q11.2 (Lindsay, 2001; Scambler, 2000). Among the In PA development, Tbx1 regulates fibroblast growth factor genes in this region, loss of the Tbx1 transcription factor is thought (Fgf) signaling by regulating the expression of Fgf8 and fibroblast to be the major etiology of DGS phenotypes in humans (Baldini, growth factor receptor 1 (Fgfr1) (Hu et al., 2004; Park et al., 2003). The spectrum of DGS pathologies includes defects in 2006). Tbx1 and Fgf8 compound heterozygotes result in more pharyngeal arch artery formation and/or remodeling, cardiac severe phenotypes than Tbx1 heterozygotes, indicating that these outflow tract and ventricular and/or atrial septal defects, thymus and genes interact genetically (Vitelli et al., 2002b). Sonic hedgehog parathyroid aplasia/hypoplasia and craniofacial anomalies (Lindsay, (Shh) promotes Tbx1 expression in the PA region through a Fox 2001; Scambler, 2000). All of these phenotypes are caused by transcription factor-dependent mechanism (Garg et al., 2001; malformation of a transient embryonic structure called the Yamagishi et al., 2003). pharyngeal apparatus (Wurdak et al., 2006). The pharyngeal Wnt proteins are highly conserved, secreted, cysteine-rich apparatus comprises pharyngeal arches (PAs) and pharyngeal glycoproteins that bind to frizzled (Fzd) receptors. In vertebrates, 19 pouches. PAs are composed of ectoderm, endoderm, neural crest- Wnt and 10 Fzd genes have been identified. Activation of Wnt derived mesenchyme and core mesoderm. Coordinated interaction signaling results in increased cytosolic b-catenin (Ctnnb1). among all of these cell types is necessary to form the tissues derived Translocation of b-catenin to the nucleus allows interactions with from the PAs. transcription factors in the T-cell factor/lymphocyte-enhancing In mice, heterozygosity of Tbx1 results in minor cardiovascular factor (Tcf/Lef) family and regulates the transcription of numerous defects, whereas Tbx1-null mice display the most severe features genes implicated in proliferation, differentiation and other cellular characteristic of DGS (Guris et al., 2001; Jerome and Papaioannou, processes (Clevers, 2006). Limited genetic evidence suggests that 2001; Lindsay et al., 2001; Merscher et al., 2001). Transgenic mice Wnt–b-catenin signaling might be involved in pharyngeal apparatus which have an additional human TBX1 gene and patients which have development. Inactivation of Wnt1 and Wnt3, as well as conditional a mutation that stabilizes the TBX1 protein also develop DGS deletion of b-catenin in neural crest-derived cells, results in neural phenotypes (Liao et al., 2004; Torres-Juan et al., 2007; Zweier et al., crest defects, including components of the first PA and cardiac 2007). This suggests that the amount of TBX1 protein is crucial for outflow tract (Brault et al., 2001). A recent study indicates that normal development and that either loss or gain of TBX1 can cause inactivation of b-catenin in anterior heart field progenitors, using DGS phenotypes. Consistent with a role in PA development, Tbx1 conditional targeting genes that are expressed early in development (e.g. Isl1-Cre, SM22-Cre and Mef2c-Cre), causes defects in the outflow tract and right ventricle by inhibiting the proliferation of Department of Developmental Biology, Washington University School of Medicine, Isl1-positive anterior heart field progenitor cells (Ai et al., 2007; St Louis, MO, USA. Cohen et al., 2007; Kwon et al., 2007; Lin et al., 2007; Qyang et al., 2007). Also, constitutive activation of -catenin signaling in anterior *Author for correspondence ([email protected]) b heart field progenitor cells causes enhanced progenitor cell Accepted 25 January 2010 proliferation and inhibition of differentiation (Ai et al., 2007; Cohen DEVELOPMENT 1138 RESEARCH ARTICLE Development 137 (7) et al., 2007; Qyang et al., 2007). The involvement of Wnt–b-catenin to the manufacturer’s instructions. Results were graphed as relative signaling in pharyngeal apparatus development is suggested by the expression compared with control, where control was scaled to 1. At least expression of b-catenin in PA mesenchyme. three independent dissections were used for each analysis. Here, we show that canonical Wnt–b-catenin signaling is active India ink injection in PA mesenchyme, where it functions to negatively regulate Mouse embryos at various stages were dissected in PBS and injected with expression of Tbx1 and downstream signaling pathways, including India ink by intra-cardiac perfusion using custom-made glass micropipettes. Fgf signaling [Fgf8, Fgfr1 and Pea3 (Etv4 – Mouse Genome Samples were fixed in 10% formalin, washed in PBS, dehydrated in a series Informatics)] and Gcm2. Mesenchymal deletion of b-catenin of graded methanol and cleared using BABB solution (1 benzyl alcohol to disrupts PA artery remodeling and neural crest cell differentiation, 2 benzyl benzoate). Samples were photographed on an Olympus SZX12 leading to abnormalities in the great vessels. Other consequences of stereo microscope. All staining patterns are representative of at least three samples. loss of b-catenin include craniofacial defects, thymic hypoplasia and detachment and mislocalization of the parathyroid gland. Wholemount immunohistochemistry Complementary gain-of-function studies show opposite effects on Embryos were isolated and fixed in 4% PFA overnight at 4°C. Samples were Tbx1 expression and downstream signaling but surprisingly similar washed and dehydrated in a series of graded methanol and stored in 100% DGS-like phenotypes. These findings indicate that Wnt–b-catenin methanol at –20°C until used. Samples were rehydrated and treated with signaling is a crucial upstream factor that regulates the level of Tbx1 H2O2 overnight at 4°C. Samples were washed with PBT, blocked with and downstream signaling molecules that are important for PA blocking solution (2% skim milk, 0.1% Triton X-100 in PBS) and incubated with a primary antibody overnight at 4°C. Samples were washed with PBT development. five times and incubated with secondary antibody conjugated with HRP overnight at 4°C. After secondary antibody incubation, samples were MATERIALS AND METHODS washed five times with PBT and developed using HRP substrate (Vector Mice Laboratories). Samples were photographed on an Olympus SZX12 stereo F/F F(DEx3)/+ lacZ/+ All mouse strains, including Ctnnb1 , Ctnnb1 , Fgf8 , microscope. Tbx1–/+, Dermo1-Cre (Twist2-Cre – Mouse Genome Informatics), Wnt1- Cre and ROSA26 reporter (R26R), have been previously described (Brault Wholemount in situ hybridization et al., 2001; Danielian et al., 1998; Grieshammer et al., 2005; Harada et Embryos were dissected in diethylpyrocarbonate (DEPC)-treated PBS and al., 1999; Jerome and Papaioannou, 2001; Soriano, 1999; Sosic et al., fixed in 4% PFA. After washing, samples were dehydrated in methanol. 2003). To inactivate Ctnnb1 in PAmesenchyme, Dermo1-Cre; Ctnnb1F/+ Samples were rehydrated and washed with hybridization solution, and mice were mated with Ctnnb1F/F mice to generate mice with the genotype incubated overnight with digoxigenin-labeled RNA probes. After washing, Ctnnb1F/F; Dermo1-Cre. These mice are referred to as Ctnnb1Dermo1-Cre. samples were incubated with anti-digoxigenin antibody conjugated with Control mice were of the genotype Ctnnb1F/F or Ctnnb1F/+; Dermo1-Cre. alkaline phosphatase (Roche) and the color reaction was performed using To inactivate Ctnnb1 in neural crest cells, Wnt1-Cre; Ctnnb1F/+ mice alkaline phosphate substrate (Roche). Samples were photographed on an were mated with Ctnnb1F/F
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