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Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

ABSTRACT: Mutations in transforming growth factor beta (TGF?) receptor type II (TGFBR2) cause Loeys-Dietz syndrome, characterized by craniofacial and cardiovascular abnormalities. Mice with a deletion of Tgfbr2 in cranial neural crest cells (Tgfbr2(fl/fl);Wnt1-Cre mice) develop cleft palate as the result of abnormal TGF? signaling activation. However, little is known about metabolic processes downstream of TGF? signaling during palatogenesis. Here, we show that Tgfbr2 mutant palatal mesenchymal cells spontaneously accumulate lipid droplets, resulting from reduced lipolysis activity. Tgfbr2 mutant palatal mesenchymal cells failed to respond to the cell proliferation stimulator sonic hedgehog, derived from the palatal epithelium. Treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor or telmisartan, a modulator of p38 MAPK activation and lipid metabolism, blocked abnormal TGF?-mediated p38 MAPK activation, restoring lipid metabolism and cell proliferation activity both in vitro and in vivo. Our results highlight the influence of alternative TGF? signaling on lipid metabolic activities, as well as how lipid metabolic defects can affect cell proliferation and adversely impact palatogenesis. This discovery has broader implications for the understanding of metabolic defects and potential prevention of congenital birth defects.

SUBMITTER: Iwata J

PROVIDER: S-EPMC3857953 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

Iwata Junichi J Suzuki Akiko A Pelikan Richard C RC Ho Thach-Vu TV Sanchez-Lara Pedro A PA Chai Yang Y

Human molecular genetics 20130823 1

Mutations in transforming growth factor beta (TGFβ) receptor type II (TGFBR2) cause Loeys-Dietz syndrome, characterized by craniofacial and cardiovascular abnormalities. Mice with a deletion of Tgfbr2 in cranial neural crest cells (Tgfbr2(fl/fl);Wnt1-Cre mice) develop cleft palate as the result of abnormal TGFβ signaling activation. However, little is known about metabolic processes downstream of TGFβ signaling during palatogenesis. Here, we show that Tgfbr2 mutant palatal mesenchymal cells spon ...[more]

PMID: 23975680

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Project description:Cleft palate is a common birth defect caused by disruption of palatogenesis during embryonic development. Although mutations disrupting components of the Wnt signaling pathway have been associated with cleft lip and palate in humans and mice, the mechanisms involving canonical Wnt signaling and its regulation in secondary palate development are not well understood. Here, we report that canonical Wnt signaling plays an important role in Pax9-mediated regulation of secondary palate development. We found that cleft palate pathogenesis in Pax9-deficient embryos is accompanied by significantly reduced expression of Axin2, an endogenous target of canonical Wnt signaling, in the developing palatal mesenchyme, particularly in the posterior regions of the palatal shelves. We found that expression of Dkk2, encoding a secreted Wnt antagonist, is significantly increased whereas the levels of active β-catenin protein, the essential transcriptional coactivator of canonical Wnt signaling, is significantly decreased in the posterior regions of the palatal shelves in embryonic day 13.5 Pax9-deficent embryos in comparison with control littermates. We show that small molecule-mediated inhibition of Dickkopf (DKK) activity in utero during palatal shelf morphogenesis partly rescued secondary palate development in Pax9-deficient embryos. Moreover, we found that genetic inactivation of Wise, which is expressed in the developing palatal shelves and encodes another secreted antagonist of canonical Wnt signaling, also rescued palate morphogenesis in Pax9-deficient mice. Furthermore, whereas Pax9del/del embryos exhibit defects in palatal shelf elevation/reorientation and significant reduction in accumulation of hyaluronic acid-a high molecular extracellular matrix glycosaminoglycan implicated in playing an important role in palatal shelf elevation-80% of Pax9del/del;Wise-/- double-mutant mouse embryos exhibit rescued palatal shelf elevation/reorientation, accompanied by restored hyaluronic acid accumulation in the palatal mesenchyme. Together, these data identify a crucial role for canonical Wnt signaling in acting downstream of Pax9 to regulate palate morphogenesis.

Project description:Cleft lip with or without cleft palate (CLP) is considered the most frequent congenital malformations of the head and neck, with cleft individuals exhibiting more chances of presenting abnormalities such as developmental defects of enamel (DDE). Matrix metallopeptidase 2 (MMP2) is a membrane-bound protein with collagen-degrading ability and has important roles in tooth formation and mineralization. The aim of this study was to evaluate the frequency, location, severity and extent of DDE found in the maxillary incisors for groups of individuals born with CLP, as well as understanding their relationship with the cleft side. Besides, this study addresses the hypothesis that DDE can be influenced by variation in the MMP2 genes (rs9923304). Individual samples, clinical history, intraoral photographs and panoramic radiographs were obtained from 233 patients under treatment at the Cleft Lip and Palate Service of the University Hospital Lauro Wanderley at the Federal University of Paraíba. Digital images were examined by the same evaluator using the Classification of Defects According to the Modified DDE Index, and then loaded into the Image Tool software, where two measurements were made: total area of the buccal surface (SA) and the area of the DDE (DA), obtaining the percentage of the surface area affected (%SAD) (ICC = 0.99). Genomic DNA was extracted from saliva samples from 124 participants. Genotyping was carried out using TaqMan chemistry for one marker in MMP2 (rs9923304). Statistical analyses were performed by The Jamovi Project software. The Shapiro-Wilk test was applied, followed by the Student's t-test and the Mann-Whitney test. Chi-square and Fisher's exact tests, and odds ratio (OR) with 95% confidence interval (CI) calculations were used to determine Hardy-Weinberg equilibrium and statistically significant differences with an alpha of 0.05. No significant differences in the prevalence and extent of enamel defects were found between male and female individuals born with CLP (p = 0.058256). The frequency of individuals presenting teeth with DDE, in relation to the cleft and non-cleft side, was statistically different (p <0.001; OR = 7.15, CI: 4.674> 7.151> 10.942). However, the averages of %SAD were similar (p = 0.18). The highest means of the %SAD were found in individuals with bilateral cleft lip with or without cleft palate (BCLP) when compared to individuals with unilateral cleft lip with or without cleft palate (UCLP), for the teeth inside (IA) and outside the cleft area (OA) (p <0.001). Regardless of the cleft side, individuals with BCLP were 7.85 times more likely to have more than one third of the tooth surface affected, showing more frequently defects in the three thirds (OA: p <0.001) (IA: p = 0.03), as well as a higher frequency of more than one type of defect (OA: p = 0.000358) (IA: p = 0.008016), whereas in UCLP, defects were isolated and restricted to only one third, more frequently, the incisal third (OA: p = 0.009) (IA: p = 0.001), with greater frequency of milder defects, such as demarcated (p = 0.02) and diffuse (p = 0.008) opacities. A higher frequency of the T allele, less common, was observed in the group of CLP individuals who had all the affected teeth or at least two teeth with %SAD greater than 20% (p = 0.019843). Our results suggest that MMP2 may have a role in the cases that presented DDE and genotyping rs9923304 could serve as the basis for a genomic approach to define risks for individuals born with CLP. Frequency and severity of DDE is strongly related to the CLP phenotype, since the highest values were found for BCLP. However, the extent of the DDE is independent of its relationship with the side of the cleft.

Dataset Information

Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

Publications

Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

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