Development of secondary palate requires strict regulation of ECM remodeling: sequential distribution of RECK, MMP-2, MMP-3, and MMP-9

Demarchi, Ana Claudia Cardoso de Oliveira; Zambuzzi, Willian Fernando; Paiva, Katiúcia Batista Silva; Silva‐Valenzuela, Maria das Graças da; Nunes, Fábio Daumas; Figueira, Rita de Cássia Sávio; Sasahara, Regina Maki; Demasi, Marcos Angelo Almeida; Winnischofer, Sheila Maria Brochado; Sogayar, Mari Cleide; Granjeiro, José Mauro

doi:10.1007/s00441-010-0931-6

Cited by 33 publications

(32 citation statements)

References 42 publications

(41 reference statements)

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“…The expression profile of Sox4 in the developing palate parallels that observed for TGF-β1 – i.e., expression in the MEE epithelium decreases significantly prior to MES formation, and is completely absent in the MES. Moreover, TGF-β is known to play a significant role in palate mesenchymal growth, eliciting changes in orofacial cell proliferation, as well as synthesis and remodeling of the extracellular matrix [50–53]. If, therefore, as has been shown elsewhere [17,19], Sox4 is a target for TGF-β signaling in the secondary palate, then a role for Sox4 in both MEE differentiation as well as mesenchymal growth can be considered.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Sox4 during Palate Development

et al. 2013

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Aim Identification of genes that contribute to secondary palate development provide a better understanding of the etiology of palatal clefts. Gene-expression profiling of the murine palate from gestational days 12–14 (GD12–14), a critical period in palate development, identified Sox4 as a differentially expressed gene. In this study, we have examined if the differential expression of Sox4 in the palate is due to changes in DNA methylation. Materials & methods In situ hybridization analysis was used to localize the expression of Sox4 in the developing murine secondary palate. CpG methylation profiling of a 1.8-kb upstream region of Sox4 in the secondary palate from GD12–14 and transfection analysis in murine embryonic maxillary mesenchymal cells using Sox4 deletion, mutant and in vitro methylated plasmid constructs were used to identify critical CpG residues regulating Sox4 expression in the palate. Results Spatiotemporal analysis revealed that Sox4 is expressed in the medial edge epithelium and presumptive rugae-forming regions of the palate from GD12 to GD13. Following palatal shelf fusion on GD14, Sox4 was expressed exclusively in the epithelia of the palatal rugae, structures that serve as signaling centers for the anteroposterior extension of the palate, and that are thought to serve as neural stem cell niches. Methylation of a 1.8-kb region upstream of Sox4, containing the putative promoter, completely eliminated promoter activity. CpG methylation profiling of the 1.8-kb region identified a CpG-poor region (DMR4) that exhibited significant differential methylation during palate development, consistent with changes in Sox4 mRNA expression. Changes in the methylation of DMR4 were attributed primarily to CpGs 83 and 85. Conclusion Our studies indicate that Sox4 is an epigenetically regulated gene that likely integrates multiple signaling systems for mediating palatal fusion, palatal extension and/or the maintenance of the neural stem cell niche in the rugae.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of Sox4 during Palate Development

et al. 2013

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“…Expression of MMPs and TIMPs mRNA and protein has been detected in the developing mouse palate, in specific spatial and temporal distribution patterns in areas where their preferred substrates are located (Morris-Wiman et al, 2000; Blavier et al, 2001; Brown et al, 2002; de Oliveira Demarchi et al, 2010). Moreover, absence of MMP activity has been shown to result in failure of palatal shelf fusion in vitro and in vivo (Blavier et al, 2001; Brown et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts

Letra

Silva

Motta

et al. 2012

Birth Defects Research

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BACKGROUND Oral clefts are common congenital anomalies and result from defects during embryogenesis. The complex etiology is evident by the number of genes and signaling pathways involved in craniofacial development. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are responsible for tissue remodeling during craniofacial development. METHODS In this study, we investigated the association of polymorphisms in 14 biologically relevant MMP and TIMP genes in 494 individuals with oral clefts and 413 control individuals from Brazil. Genotypes were generated using Taqman chemistry. Analyses were performed using PLINK software. RESULTS Polymorphisms in MMP3 (rs522616) and TIMP2 (rs8179096) showed significant association with all cleft types (all clefts, cleft lip/palate, and cleft palate; p ≤ 0.002). An additional family‐based dataset (881 case‐parent trios) from the United States was used for confirmation of the association findings (p < 0.05). Analysis of gene‐gene interaction suggests that MMP3 and TIMP2 may interactively contribute to a cleft phenotype. CONCLUSIONS This study provides new evidence that variation in MMP3 may contribute to nonsyndromic oral clefts and further supports the involvement of TIMP2 as a cleft susceptibility gene. Although additional studies are still necessary to unveil the exact mechanism by which MMP3 and TIMP2 would contribute to a cleft phenotype, allelic polymorphisms in these genes and their interactions may partly explain the variance of individual susceptibility to oral clefts. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.

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“…The synthesis and degradation of the extracellular matrix in the secondary palate has been proposed to be necessary for palatal shelf elevation [30] and although the spatio-temporal expression patterns of many extracellular constituents in the developing secondary palate have been characterized [31, 32], a complete description of the individual molecules is lacking. While the regulation of these molecules requires additional clarification, it is recognized that tight control is critical for normal palate development [33]. Coordinated regulation of both apoptosis and extracellular matrix metabolism is necessary for proper growth and elevation of the palatal shelves and the work described in the current paper suggests that crosstalk between the TGFβ and Wnt signaling pathways may be an important means of regulation for both of these processes.…”

Section: Discussionmentioning

confidence: 91%

TGFβ-1 and Wnt-3a interact to induce unique gene expression profiles in murine embryonic palate mesenchymal cells

Warner

Mukhopadhyay

Brock

et al. 2011

Reproductive Toxicology

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Development of the secondary palate in mammals is a complex process under the control of numerous growth and differentiation factors that regulate key processes such as cell proliferation, synthesis of extracellular matrix molecules, and epithelial-mesenchymal transdifferentiation. Alterations in any one of these processes either through genetic mutation or environmental insult have the potential to lead to clefts of the secondary palate. Members of the TGFβ family of cytokines are crucial mediators of these processes and emerging evidence supports a pivotal role for members of the Wnt family of secreted growth and differentiation factors. Previous work in this laboratory demonstrated cross-talk between the Wnt and TGFβ signaling pathways in cultured mouse embryonic palate mesenchymal cells. In the current study we tested the hypothesis that unique gene expression profiles are induced in murine embryonic palate mesenchymal cells as a result of this cross-talk between the TGFβ and Wnt signal transduction pathways.

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Development of secondary palate requires strict regulation of ECM remodeling: sequential distribution of RECK, MMP-2, MMP-3, and MMP-9

Cited by 33 publications

References 42 publications

Epigenetic Regulation of Sox4 during Palate Development

Epigenetic Regulation of Sox4 during Palate Development

Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts

TGFβ-1 and Wnt-3a interact to induce unique gene expression profiles in murine embryonic palate mesenchymal cells

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