Cadherins as Targets for Genetic Diseases

El-Amraoui, Aziz; Petit, Christine

doi:10.1101/cshperspect.a003095

Cited by 48 publications

(31 citation statements)

References 105 publications

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“…Several studies have shown that cadherin molecules play a central role in epithelial integrity and tissue morphogenesis (16,17), and moreover, that dysregulation of cadherin is linked to a number of diseases, including cancer (23,43,44). The classical cadherins represent the main cadherin family present in cell-cell junctions and include E-cadherin, VE cadherin, and N-cadherin.…”

Section: Discussionmentioning

confidence: 99%

N-cadherin relocalization during cardiac trabeculation

Cherian

Fukuda

Augustine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During cardiac trabeculation, cardiomyocytes delaminate from the outermost (compact) layer to form complex muscular structures known as trabeculae. As these cardiomyocytes delaminate, the remodeling of adhesion junctions must be tightly coordinated so cells can extrude from the compact layer while remaining in tight contact with their neighbors. In this study, we examined the distribution of N-cadherin (Cdh2) during cardiac trabeculation in zebrafish. By analyzing the localization of a Cdh2-EGFP fusion protein expressed under the control of the zebrafish cdh2 promoter, we initially observed Cdh2-EGFP expression along the lateral sides of embryonic cardiomyocytes, in an evenly distributed pattern, and with the occasional appearance of punctae. Within a few hours, Cdh2-EGFP distribution on the lateral sides of cardiomyocytes evolves into a clear punctate pattern as Cdh2-EGFP molecules outside the punctae cluster to increase the size of these aggregates. In addition, Cdh2-EGFP molecules also appear on the basal side of cardiomyocytes that remain in the compact layer. Delaminating cardiomyocytes accumulate Cdh2-EGFP on the surface facing the basal side of compact layer cardiomyocytes, thereby allowing tight adhesion between these layers. Importantly, we find that blood flow/cardiac contractility is required for the transition from an even distribution of Cdh2-EGFP to the formation of punctae. Furthermore, using time-lapse imaging of beating hearts in conjunction with a Cdh2 tandem fluorescent protein timer transgenic line, we observed that Cdh2-EGFP molecules appear to move from the lateral to the basal side of cardiomyocytes along the cell membrane, and that Erb-b2 receptor tyrosine kinase 2 (Erbb2) function is required for this relocalization.T o maximize its function, the heart undergoes a series of morphological changes during development, with trabeculation being one of the main processes (1-5). Trabeculae initially appear as myocardial ridges in the outer curvature of the ventricle, and they are important for cardiac function, as evidenced by studies of hypo-and hypertrabeculation models (3,(6)(7)(8)(9)(10)(11). Previous studies have shown that Erbb2 signaling is essential for trabeculation (3,6,7,10,11). Moreover, disturbing blood flow or cardiac contractility in the ventricle perturbs trabeculation (4, 12, 13), suggesting an important role for mechanical forces in this process. Our understanding of the cellular mechanisms regulating trabeculation remains fairly limited. Cardiomyocytes in the early heart tube show an epithelium-like morphology (3,14). During trabeculation, some cardiomyocytes delaminate and enter the trabecular layer, where they join other trabecular cardiomyocytes to form ridge-like structures (3,15). Previous studies have shown that the most proximal cardiomyocytes in the trabecular layer remain tightly attached to the basal side of compact layer cardiomyocytes (3, 15). Some of the key molecules involved in cellcell adhesion belong to the cadherin family, and they also play crucial roles in...

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Section: Discussionmentioning

confidence: 99%

N-cadherin relocalization during cardiac trabeculation

Cherian

Fukuda

Augustine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Up to now, certain cadherin or catenin genes have been assigned as major genes causative of specific diseases (see also review in Ref. 82). Furthermore, recent advancements in genome-wide analysis are making it possible to identify various cadherin/cadherin-related genes as susceptibility genes or risk factors for particular neural disorders (96).…”

Section: E Cadherin Deficiency Related To Brain Diseasesmentioning

confidence: 99%

“…Harmonin is an adaptor protein with three PDZ domains, and it also interacts with F-actin and another adaptor protein, Sans (USH1G), suggesting this molecule to be involved in cytoskeleton assembly. On the other hand, myosin 7a and Sans are required for transportation of harmonin-␤ into stereocilia (82). Moreover, the mechanotransducer channel, the structure of which has not been determined yet, is localized at Pcdh15 side (i.e., lower part) of the tip links, and myosin 7a may be involved in gating mechanotransduction channels (32,134,174).…”

Section: B Cadherin 23 and Protocadherin 15 In Inner Ear Functionsmentioning

confidence: 99%

Cadherins in Brain Morphogenesis and Wiring

Hirano

Takeichi

2012

Physiological Reviews

266

312

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LHirano S, Takeichi M. Cadherins in Brain Morphogenesis and Wiring. Physiol Rev 92: 597-634, 2012; doi:10.1152/physrev.00014.2011 -dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. Various cadherin-related molecules have also been identified, which show diverse functions, not only for the regulation of cell adhesion but also for that of cell proliferation and planar cell polarity. During the past decade, understanding of the roles of these molecules in the nervous system has significantly progressed. They are important not only for the development of the nervous system but also for its functions and, in turn, for neural disorders. In this review, we discuss the roles of cadherins and related molecules in neural development and function in the vertebrate brain.

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“…More recently, DSG4 gene mutations were found to be associated with human monilethrix hairs (Shimomura et al, 2006;Amagai, 2010). These studies convincingly demonstrate that DSG4 plays an important role in regulating the proliferation and differentiation of hair follicles in mammals (Schaffer et al, 2006;El-Amraoui and Petit, 2010). Although our knowledge about the sheep DSG4 gene remains limited, some DNA sequences of sheep that are homologous to this gene in other organisms are available in the GenBank.…”

Section: Introductionmentioning

confidence: 98%

“…DSG4 plays an important role in regulating the development and differentiation of hair follicles (Owens et al, 2008;Zhang et al, 2008;Bazzi et al, 2009). Since the discovery of this gene (Kljuic et al, 2003), a number of mutations in the DSG4 gene have been reported to induce a group of hair disorders in mammals (Zhang et al, 2008;Amagai, 2010;El-Amraoui and Petit, 2010); thus, this gene may be considered as a potential candidate that influences wool traits. The human DSG4 is composed of 5 homologous extracellular domains, a transmembrane domain, and a carboxy-terminal cytoplasmic tail (Whittock and Bower, 2003).…”

Section: Dsg4 Gene a Novel Candidate For Wool Traitsmentioning

confidence: 99%

Identification of complete linkage disequilibrium in the DSG4 gene and its association with wool length and crimp in Chinese indigenous sheep

Ling¹,

Xiang²,

Zhang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The desmoglein 4 (DSG4) gene is a potential candidate in the search for genes that may affect wool traits, because of its function. This study aimed to screen for polymorphisms in partial exon 16 and 3ꞌUTR of the sheep desmoglein 4 DSG4 gene, and to test its possible association with wool length and crimp associated with fur. Overall, 326 sheep were scanned via single-strand conformational polymorphism assay, through three pairs of primers. The breeds included Tan, Han, and TanxHan from China, Polled Dorset from Australia, and Suffolk from Britain genotypes AA, BB, and AB for primer2 and genotypes DD, EE, and DE for primer3 were detected in native breeds. Six SNPs and 3-bp insertion/deletions were found in exon 16, of which 4 lead to amino acid substitutions. In addition, 1 SNP was found in 3ꞌUTR. The DSG4 genotype was found to be strongly associated with all wool traits that were considered in this study (P < 0.01). Sheep with the genotype MM had a higher least square mean compared to sheep with the genotype WW or WM with respect to birth scapular wool length (P < 0.01), crimp number of birth scapular wool crimp (P < 0.01), crimp number of weaning scapular wool crimp (P < 0.01), and crimp number of weaning rump wool crimp (P < 0.01, P < 0.05). In conclusion, our study is the first to demonstrate that the DSG4 gene may be a candidate, or major gene, which influences important wool traits.

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Cadherins as Targets for Genetic Diseases

Cited by 48 publications

References 105 publications

N-cadherin relocalization during cardiac trabeculation

N-cadherin relocalization during cardiac trabeculation

Cadherins in Brain Morphogenesis and Wiring

Identification of complete linkage disequilibrium in the DSG4 gene and its association with wool length and crimp in Chinese indigenous sheep

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