Functional Significance of <i>MMP3</i> and <i>TIMP2</i> Polymorphisms in Cleft Lip/Palate

Letra, Ariadne; Zhao, Min; Silva, Renato; Vieira, Alexandre R.; Hecht, Jacqueline

doi:10.1177/0022034514534444

Cited by 20 publications

(23 citation statements)

References 26 publications

(46 reference statements)

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“…Surprisingly, and contrary to data in mice, none of the syndromes linked to mutations in genes encoding secreted metalloproteases of the MMP family are associated with a cleft palate phenotype. However, we propose a link may exist since some promoter polymorphisms for MMP3 and TIMP2 were linked with the condition (Letra et al, ), which may warrant their addition to the list in the future.…”

Section: Ecm Expression During Palatal Growthmentioning

confidence: 99%

Extracellular Matrix in Secondary Palate Development

Logan

Ruest

Benson

et al. 2019

The Anatomical Record

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The secondary palate arises from outgrowths of epithelia-covered embryonic mesenchyme that grow from the maxillary prominence, remodel to meet over the tongue, and fuse at the midline. These events require the coordination of cell proliferation, migration, and gene expression, all of which take place in the context of the extracellular matrix (ECM). Palatal cells generate their ECM, and then stiffen, degrade, or otherwise modify its properties to achieve the required cell movement and organization during palatogenesis. The ECM, in turn, acts on the cells through their matrix receptors to change their gene expression and thus their phenotype. The number of ECM-related gene mutations that cause cleft palate in mice and humans is a testament to the crucial role the matrix plays in palate development and a reminder that understanding that role is vital to our progress in treating palate deformities. This article will review the known ECM constituents at each stage of palatogenesis, the mechanisms of tissue reorganization and cell migration through the palatal ECM, the reciprocal relationship between the ECM and gene expression, and human syndromes with cleft palate that arise from mutations of ECM proteins and their regulators. Anat Rec, 303:1543Rec, 303: -1556Rec, 303: , 2020

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Section: Ecm Expression During Palatal Growthmentioning

confidence: 99%

Extracellular Matrix in Secondary Palate Development

Logan

Ruest

Benson

et al. 2019

The Anatomical Record

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“…In contrast, a fourfold increased activity was found with the 6A_G promoter. The 6A_A haplotype was the least active promoter, suggesting potential gene downregulation with this allelic combination (Letra et al, 2014). Taken together, these observations indicate that the -709 A/G variant may directly regulate MMP3 promoter activity, although its function was shown to the driven by the 1171 5A/6A alleles in the background.…”

Section: Ecm Remodeling Enzymes As Candidate Genes For Orofacial Cleftsmentioning

confidence: 79%

“…Furthermore, both C and T alleles were found to be putative binding sites for NFκB, a key transcription factor involved in the innate immune system. While C and T alleles reduced binding capability when NFκB consensus binding oligo diverges from protein in the same reaction, introduction of a mutant NFκB immunized C and T alleles from binding abolition (Letra et al, 2014). Additional studies are still necessary to unveil the exact mechanisms by which MMPs and TIMPs might contribute to NSCLP; nonetheless, allelic polymorphisms in these genes and their interactions may partly explain the variance in individual susceptibility to oral clefts.…”

Section: Ecm Remodeling Enzymes As Candidate Genes For Orofacial Cleftsmentioning

confidence: 99%

Extracellular Matrix Composition and Remodeling: Current Perspectives on Secondary Palate Formation, Cleft Lip/Palate, and Palatal Reconstruction

Paiva

Maas

Santos

et al. 2019

Front. Cell Dev. Biol.

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Craniofacial development comprises a complex process in humans in which failures or disturbances frequently lead to congenital anomalies. Cleft lip with/without palate (CL/P) is a common congenital anomaly that occurs due to variations in craniofacial development genes, and may occur as part of a syndrome, or more commonly in isolated forms (non-syndromic). The etiology of CL/P is multifactorial with genes, environmental factors, and their potential interactions contributing to the condition. Rehabilitation of CL/P patients requires a multidisciplinary team to perform the multiple surgical, dental, and psychological interventions required throughout the patient's life. Despite progress, lip/palatal reconstruction is still a major treatment challenge. Genetic mutations and polymorphisms in several genes, including extracellular matrix (ECM) genes, soluble factors, and enzymes responsible for ECM remodeling (e.g., metalloproteinases), have been suggested to play a role in the etiology of CL/P; hence, these may be considered likely targets for the development of new preventive and/or therapeutic strategies. In this context, investigations are being conducted on new therapeutic approaches based on tissue bioengineering, associating stem cells with biomaterials, signaling molecules, and innovative technologies. In this review, we discuss the role of genes involved in ECM composition and remodeling during secondary palate formation and pathogenesis and genetic etiology of CL/P. We also discuss potential therapeutic approaches using bioactive molecules and principles of tissue bioengineering for state-of-the-art CL/P repair and palatal reconstruction.

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“…Interestingly, both Casp8 and Mmp2 genes have been shown to play a role in craniofacial development (Ahi et al, 2014;Ekbote et al, 2014;Huang et al, 2011;Mosig et al, 2007;Smane et al, 2013). Moreover, MMP gene variants have been significantly associated with NSCL/P and shown as functionally relevant to this condition (Letra et al, 2007(Letra et al, , 2012(Letra et al, , 2014.…”

Section: Resultsmentioning

confidence: 99%

Crispld2 is required for neural crest cell migration and cell viability during zebrafish craniofacial development

Swindell¹,

Yuan²,

Maili³

et al. 2015

Genesis

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Summary The CAP superfamily member, CRISPLD2, has previously been shown to be associated with nonsyndromic cleft lip and palate (NSCLP) in human populations and to be essential for normal craniofacial development in the zebrafish. Additionally, in rodent models, CRISPLD2 has been shown to play a role in normal lung and kidney development. However, the specific role of CRISPLD2 during these developmental processes has yet to be determined. In this study, it was demonstrated that Crispld2 protein localizes to the orofacial region of the zebrafish embryo and knockdown of crispld2 resulted in abnormal migration of neural crest cells (NCCs) during both early and late time points. An increase in cell death after crispld2 knockdown as well as an increase in apoptotic marker genes was also shown. This data suggests that Crispld2 modulates the migration, differentiation, and/or survival of NCCs during early craniofacial development. These results indicate an important role for Crispld2 in NCC migration during craniofacial development and suggests involvement of Crispld2 in cell viability during formation of the orofacies. genesis 53:660–667, 2015.

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Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate

Cited by 20 publications

References 26 publications

Extracellular Matrix in Secondary Palate Development

Extracellular Matrix in Secondary Palate Development

Extracellular Matrix Composition and Remodeling: Current Perspectives on Secondary Palate Formation, Cleft Lip/Palate, and Palatal Reconstruction

Crispld2 is required for neural crest cell migration and cell viability during zebrafish craniofacial development

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