Abstract:Introduction Frontonasal dysplasia (FND) consists of a group of disorders characterized by ocular hypertelorism, midline facial cleft affecting the nose and/or upper lip and palate, notching or clefting of the alae nasi, and it is sometimes associated with anterior cranium bifidum and other malformations (Wu et al. 2007; Kayserili et al. 2009; Twigg et al. 2009). Although it has long been recognized that FND results from abnormal development of the embryonic frontonasal prominence, which forms from cranial neu… Show more
“…Six1 −/− Six4 −/− embryos have been shown to exhibit small maxillary and mandibular processes and abnormal frontonasal process and tongue formation 15,37,52 . A patterning defect was observed in the Six1 −/− maxillary/mandibular boundary region and enhanced in Six1 −/− Six2 +/− embryos 24,53 . In tooth development of Six1 −/− mice, anomalies in epithelial invagination were observed only in lower incisors but not in molars or upper incisors (Kawasaki et al 26 ; unpublished data).…”
Background
The structure of the mouse incisor is characterized by its asymmetric accumulation of enamel matrix proteins on the labial side. The asymmetric structure originates from the patterning of the epithelial incisor placode through the interaction with dental mesenchymal cells. However, the molecular basis for the asymmetric patterning of the incisor germ is largely unknown.
Results
A homeobox transcription factor SIX1 was shown to be produced in the mandibular mesenchyme, and its localization patterns changed dynamically during lower incisor development. Six1−/− mice exhibited smaller lower incisor primordia than wild‐type mice. Furthermore, Six1−/− mice showed enamel matrix production on both the lingual and labial sides and disturbed odontoblast maturation. In the earlier stages of development, the formation of signaling centers, the initiation knot and the enamel knot, which are essential for the morphogenesis of tooth germs, were impaired in Six1−/− embryos. Notably, Wnt signaling activity, which shows an anterior‐posterior gradient, and the expression patterns of genes involved in incisor formation were altered in the mesenchyme in Six1−/− embryos.
Conclusion
Our results indicate that Six1 is required for signaling center formation in lower incisor germs and the labial‐lingual asymmetry of the lower incisors by regulating the anterior‐posterior patterning of the mandibular mesenchyme.
“…Six1 −/− Six4 −/− embryos have been shown to exhibit small maxillary and mandibular processes and abnormal frontonasal process and tongue formation 15,37,52 . A patterning defect was observed in the Six1 −/− maxillary/mandibular boundary region and enhanced in Six1 −/− Six2 +/− embryos 24,53 . In tooth development of Six1 −/− mice, anomalies in epithelial invagination were observed only in lower incisors but not in molars or upper incisors (Kawasaki et al 26 ; unpublished data).…”
Background
The structure of the mouse incisor is characterized by its asymmetric accumulation of enamel matrix proteins on the labial side. The asymmetric structure originates from the patterning of the epithelial incisor placode through the interaction with dental mesenchymal cells. However, the molecular basis for the asymmetric patterning of the incisor germ is largely unknown.
Results
A homeobox transcription factor SIX1 was shown to be produced in the mandibular mesenchyme, and its localization patterns changed dynamically during lower incisor development. Six1−/− mice exhibited smaller lower incisor primordia than wild‐type mice. Furthermore, Six1−/− mice showed enamel matrix production on both the lingual and labial sides and disturbed odontoblast maturation. In the earlier stages of development, the formation of signaling centers, the initiation knot and the enamel knot, which are essential for the morphogenesis of tooth germs, were impaired in Six1−/− embryos. Notably, Wnt signaling activity, which shows an anterior‐posterior gradient, and the expression patterns of genes involved in incisor formation were altered in the mesenchyme in Six1−/− embryos.
Conclusion
Our results indicate that Six1 is required for signaling center formation in lower incisor germs and the labial‐lingual asymmetry of the lower incisors by regulating the anterior‐posterior patterning of the mandibular mesenchyme.
“…Embryos and pups for histological analysis, in situ hybridization, and skeletal preparation were collected and processed as previously described 27 . Immunofluorescent staining of tongue muscles was performed with Anti‐muscle Actin monoclonal antibody (1:1000, Clone HUC1‐1, generously provided by Dr. James Lessard, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio) 28 and goat anti‐mouse secondary antibody (1:1000, Alexa Fluor A11001, Lot#1484573, Life Technologies, Eugene, Oregon) on 8 μm‐thick serial paraffin sections following the protocol described previously 29 .…”
Section: Methodsmentioning
confidence: 99%
“…All animal work procedures were performed following recommendations in the Guide for Care and Use of Laboratory Animals by the National Institutes 3.2 | Histology, in situ hybridization, skeletal preparation, and immunofluorescent staining Embryos and pups for histological analysis, in situ hybridization, and skeletal preparation were collected and processed as previously described. 27 Immunofluorescent staining of tongue muscles was performed with Antimuscle Actin monoclonal antibody (1:1000, Clone HUC1-1, generously provided by Dr. James Lessard, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio) 28 and goat anti-mouse secondary antibody (1:1000, Alexa Fluor A11001, Lot#1484573, Life Technologies, Eugene, Oregon) on 8 μm-thick serial paraffin sections following the protocol described previously. 29 Images were taken using a Nikon DS-Qi2 microscope (Nikon Instruments Inc., Melville, New York), and the autofluorescence of blood cells was removed with the image operations function of the NIS-Elements AR 4.30.03 64-bit software (Nikon Instruments Inc., Melville, New York).…”
Background: Previous studies showed that mice lacking Fgf18 function had cleft palate defects and that the FGF18 locus was associated with cleft lip and palate in humans, but what specific roles Fgf18 plays during palatogenesis are unclear.Results: We show that Fgf18 exhibits regionally restricted expression in developing palatal shelves, mandible, and tongue, during palatal outgrowth and fusion in mouse embryos. Tissue-specific inactivation of Fgf18 throughout neural crest-derived craniofacial mesenchyme caused shortened mandible and reduction in ossification of the frontal, nasal, and anterior cranial base skeletal elements in Fgf18 c/c ;Wnt1-Cre mutant mice. About 64% of Fgf18 c/c ;Wnt1-Cre mice exhibited cleft palate. Whereas palatal shelf elevation was impaired in many Fgf18 c/c ;Wnt1-Cre embryos, no significant difference in palatal cell proliferation was detected between Fgf18 c/c ;Wnt1-Cre embryos and their control littermates. Embryonic maxillary explants from Fgf18 c/c ;Wnt1-Cre embryos showed successful palatal shelf elevation and fusion in organ culture similar to the maxillary explants from control embryos. Furthermore, tissue-specific inactivation of Fgf18 in the early palatal mesenchyme did not cause cleft palate.
Conclusion:These results demonstrate a critical role for Fgf18 expression in the neural crest-derived mesenchyme for the development of the mandible and multiple craniofacial bones but Fgf18 expression in the palatal mesenchyme is dispensable for palatogenesis.
“…2c ). For example, SIX1 and SIX2 played a crucial neural crest cell-autonomous role in frontonasal morphogenesis 34 ; ZIC1 was responsible for triggering the early neural crest gene regulatory network by direct activation of multiple key neural crest specifiers 35 , such as SNAI1/2 , FOXD3 , and TWIST1 . Fig.…”
Cranial Neural Crest Cells (CNCC) originate at the cephalic region from forebrain, midbrain and hindbrain, migrate into the developing craniofacial region, and subsequently differentiate into multiple cell types. The entire specification, delamination, migration, and differentiation process is highly regulated and abnormalities during this craniofacial development cause birth defects. To better understand the molecular networks underlying CNCC, we integrate paired gene expression & chromatin accessibility data and reconstruct the genome-wide human Regulatory network of CNCC (hReg-CNCC). Consensus optimization predicts high-quality regulations and reveals the architecture of upstream, core, and downstream transcription factors that are associated with functions of neural plate border, specification, and migration. hReg-CNCC allows us to annotate genetic variants of human facial GWAS and disease traits with associated cis-regulatory modules, transcription factors, and target genes. For example, we reveal the distal and combinatorial regulation of multiple SNPs to core TF ALX1 and associations to facial distances and cranial rare disease. In addition, hReg-CNCC connects the DNA sequence differences in evolution, such as ultra-conserved elements and human accelerated regions, with gene expression and phenotype. hReg-CNCC provides a valuable resource to interpret genetic variants as early as gastrulation during embryonic development. The network resources are available at https://github.com/AMSSwanglab/hReg-CNCC.
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