Cleft palate formation after palatal fusion occurs due to the rupture of epithelial basement membranes

2018 ◽  
Vol 46 (12) ◽  
pp. 2027-2031 ◽  
Author(s):  
Chisato Sakuma ◽  
Hideto Imura ◽  
Tomohiro Yamada ◽  
Toshio Sugahara ◽  
Azumi Hirata ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Basement Membranes ◽  
Palatal Fusion ◽  
Epithelial Basement

Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions

Development ◽  
2001 ◽  
Vol 128 (6) ◽  
pp. 883-894 ◽  
Author(s):  
B.E. Vogel ◽  
E.M. Hedgecock
Keyword(s):  
Matrix Protein ◽  
Chromosome Instability ◽  
Basement Membranes ◽  
Extracellular Matrix Protein ◽  
Immunoglobulin Superfamily ◽  
Cell Contact ◽  
Chromosome Loss ◽  
Oriented Line ◽  
Escape Reflex ◽  
Epithelial Basement

him-4 mutations cause a novel syndrome of tissue fragility, defective cell migration and chromosome instability in Caenorhabditis elegans. Null mutants have abnormal escape reflex, mispositioning of the vas deferens and uterus, and mitotic chromosome loss and multinucleate cells in the germline. The him-4 gene product, hemicentin, is a conserved extracellular matrix protein with 48 tandem immunoglobulin repeats flanked by novel terminal domains. Secreted from skeletal muscle and gonadal leader cells, hemicentin assembles into fine tracks at specific sites, where it contracts broad regions of cell contact into oriented linear junctions. Some tracks organize hemidesmosomes in the overlying epidermis. Hemicentin tracks facilitate mechanosensory neuron anchorage to the epidermis, gliding of the developing gonad along epithelial basement membranes and germline cellularization.

Pathogenesis of cleft palate in TGF-beta3 knockout mice

Development ◽  
1999 ◽  
Vol 126 (17) ◽  
pp. 3869-3879 ◽  
Author(s):  
Y. Taya ◽  
S. O'Kane ◽  
M.W. Ferguson
Keyword(s):  
Organ Culture ◽  
Cleft Palate ◽  
Transforming Growth Factor ◽  
Outer Cell ◽  
Complete Disappearance ◽  
Surface Receptors ◽  
Palatal Fusion ◽  
Medial Edge

We previously reported that mutation of the transforming growth factor-beta3 (TGF-beta3) gene caused cleft palate in homozygous null (−/−) mice. TGF-beta3 is normally expressed in the medial edge epithelial (MEE) cells of the palatal shelf. In the present study, we investigated the mechanisms by which TGF-beta3 deletions caused cleft palate in 129 × CF-1 mice. For organ culture, palatal shelves were dissected from embryonic day 13.5 (E13.5) mouse embryos. Palatal shelves were placed singly or in pairs on Millipore filters and cultured in DMEM/F12 medium. Shelves were placed in homologous (+/+ vs +/+, −/− vs −/−, +/− vs +/−) or heterologous (+/+ vs −/−, +/− vs −/−, +/+ vs +/−) paired combinations and examined by macroscopy and histology. Pairs of −/− and −/− shelves failed to fuse over 72 hours of culture whereas pairs of +/+ (wild-type) and +/+ or +/− (heterozygote) and +/−, as well as +/+ and −/− shelves, fused within the first 48 hour period. Histological examination of the fused +/+ and +/+ shelves showed complete disappearance of the midline epithelial seam whereas −/− and +/+ shelves still had some seam remnants. In order to investigate the ability of TGF-beta family members to rescue the fusion between −/− and −/− palatal shelves in vitro, either recombinant human (rh) TGF-beta1, porcine (p) TGF-beta2, rh TGF-beta3, rh activin, or p inhibin was added to the medium in different concentrations at specific times and for various periods during the culture. In untreated organ culture −/− palate pairs completely failed to fuse, treatment with TGF-beta3 induced complete palatal fusion, TGF-beta1 or TGF-beta2 near normal fusion, but activin and inhibin had no effect. We investigated ultrastructural features of the surface of the MEE cells using SEM to compare TGF-beta3-null embryos (E 12. 5-E 16.5) with +/+ and +/− embryos in vivo and in vitro. Up to E13.5 and after E15.5, structures resembling short rods were observed in both +/+ and −/− embryos. Just before fusion, at E14.5, a lot of filopodia-like structures appeared on the surface of the MEE cells in +/+ embryos, however, none were observed in −/− embryos, either in vivo or in vitro. With TEM these filopodia are coated with material resembling proteoglycan. Interestingly, addition of TGF-beta3 to the culture medium which caused fusion between the −/− palatal shelves also induced the appearance of these filopodia on their MEE surfaces. TGF-beta1 and TGF-beta2 also induced filopodia on the −/− MEE but to a lesser extent than TGF-beta3 and additionally induced lamellipodia on their cell surfaces. These results suggest that TGF-beta3 may regulate palatal fusion by inducing filopodia on the outer cell membrane of the palatal medial edge epithelia prior to shelf contact. Exogenous recombinant TGF-beta3 can rescue fusion in −/− palatal shelves by inducing such filopodia, illustrating that the effects of TGF-beta3 are transduced by cell surface receptors which raises interesting potential therapeutic strategies to prevent and treat embryonic cleft palate.

scholarly journals Loss of surface and cyst epithelial basement membranes and preneoplastic morphologic changes in prophylactic oophorectomies

Cancer ◽  
2003 ◽  
Vol 98 (12) ◽  
pp. 2607-2623 ◽  
Author(s):  
Isabelle H. Roland ◽  
Wan-Lin Yang ◽  
Dong-Hua Yang ◽  
Mary B. Daly ◽  
Robert F. Ozols ◽  
...  
Keyword(s):  
Basement Membranes ◽  
Epithelial Basement ◽  
Morphologic Changes

scholarly journals Role of Cell Surface Metalloprotease Mt1-Mmp in Epithelial Cell Migration over Laminin-5

2000 ◽  
Vol 148 (3) ◽  
pp. 615-624 ◽  
Author(s):  
Naohiko Koshikawa ◽  
Gianluigi Giannelli ◽  
Vincenzo Cirulli ◽  
Kaoru Miyazaki ◽  
Vito Quaranta
Keyword(s):  
Cell Lines ◽  
Cancer Metastasis ◽  
Gelatin Zymography ◽  
Basement Membranes ◽  
Cancer Tissue ◽  
Laminin 5 ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Tissue Specimens ◽  
Epithelial Basement

Laminin-5 (Ln-5) is an extracellular matrix substrate for cell adhesion and migration, which is found in many epithelial basement membranes. Mechanisms eliciting migration on Ln-5 need to be elucidated because of their relevance to tissue remodeling and cancer metastasis. We showed that exogenous addition of activated matrix metalloprotease (MMP) 2 stimulates migration onto Ln-5 in breast epithelial cells via cleavage of the γ2 subunit. To investigate the biological scope of this proteolytic mechanism, we tested a panel of cells, including colon and breast carcinomas, hepatomas, and immortalized hepatocytes, selected because they migrated or scattered constitutively in the presence of Ln-5. We found that constitutive migration was inhibited by BB94 or TIMPs, known inhibitors of MMPs. Limited profiling by gelatin zymography and Western blotting indicated that the ability to constitutively migrate on Ln-5 correlated with expression of plasma membrane bound MT1-MMP metalloprotease, rather than secretion of MMP2, since MMP2 was not produced by three cell lines (one breast and two colon carcinomas) that constitutively migrated on Ln-5. Moreover, migration on Ln-5 was reduced by MT1-MMP antisense oligonucleotides both in MMP2+ and MMP2− cell lines. MT1-MMP directly cleaved Ln-5, with a pattern similar to that of MMP2. The hemopexin-like domain of MMP2, which interferes with MMP2 activation, reduced Ln-5 migration in MT1-MMP+, MMP2+ cells, but not in MT1-MMP+, MMP2− cells. These results suggest a model whereby expression of MT1-MMP is the primary trigger for migration over Ln-5, whereas MMP2, which is activated by MT1-MMP, may play an ancillary role, perhaps by amplifying the MT1-MMP effects. Codistribution of MT1-MMP with Ln-5 in colon and breast cancer tissue specimens suggested a role for this mechanism in invasion. Thus, Ln-5 cleavage by MMPs may be a widespread mechanism that triggers migration in cells contacting epithelial basement membranes.

scholarly journals Ras signaling and its effector RREB1 are required for the dissociation of MEE cells in palatogenesis

2021 ◽  
Author(s):  
Toshihiro Inubushi ◽  
Ayaka Fujiwara ◽  
Takumi Hirose ◽  
Gozo Aoyama ◽  
Toshihiro Uchihashi ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Organ Culture ◽  
Cleft Palate ◽  
Birth Defects ◽  
Crucial Role ◽  
Initial Step ◽  
Ras Signaling ◽  
Palatal Fusion ◽  
Element Binding Protein ◽  
Responsive Element

Cleft palate is one of the major congenital craniofacial birth defects. The etiology underlying the pathogenesis of cleft palate has largely remained unelucidated. Dissociation of the medial edge epithelium (MEE) at the contacting region of palatal shelves and subsequent migration or apoptosis of MEE cells is required for the proper MEE removal. Ras Responsive Element Binding Protein 1 (RREB1), a RAS transcriptional effector, has recently been shown to play a crucial role in developmental EMT, in which loss of epithelial characteristics is an initial step, during mid-gastrulation of embryonic development. Interestingly, the involvement of RREB1 in cleft palate has been indicated in humans. Here, we demonstrated that pan-Ras inhibitor prevents the dissociation of MEE during palatal fusion. Rreb1 is expressed in the palatal epithelium during palatal fusion, and knockdown of Rreb1 in palatal organ culture resulted in palatal fusion defects by inhibiting the dissociation of MEE cells. Our present findings provide evidence that RREB1-mediated Ras signaling is required during palatal fusion. Aberrant RREB1-mediated Ras signaling might be involved in the pathogenesis of cleft palate.

scholarly journals DNA hypermethylation of Fgf16 and Tbx22 associated with cleft palate during palatal fusion

2019 ◽  
Vol 27 ◽  
Author(s):  
Xuan Shu ◽  
Zejun Dong ◽  
Liuhanghang Cheng ◽  
Shenyou Shu
Keyword(s):  
Cleft Palate ◽  
Dna Hypermethylation ◽  
Palatal Fusion

Ultrastructural localization of Fras1 in the sublamina densa of embryonic epithelial basement membranes

2007 ◽  
Vol 299 (7) ◽  
pp. 337-343 ◽  
Author(s):  
Yannis Dalezios ◽  
Babis Papasozomenos ◽  
Petros Petrou ◽  
Georges Chalepakis
Keyword(s):  
Ultrastructural Localization ◽  
Basement Membranes ◽  
Epithelial Basement
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