Genome-wide association study on craniofacial microsomia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69664 | GEO | 2016/02/03
SECONDARY ACCESSION(S): PRJNA286132
REPOSITORIES: GEO
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Project description:Congenital malformations in facial bones significantly impact the overall representation of face. Establishing a correlation between gene expression and morphogenesis of craniofacial structures may lead to new discoveries of molecular mechanisms of craniofacial development. Thus in the present investigation we will generate gene expression profiles of different facial bones at different time intervals over a period of 5 years to establish their roles in regulating craniofacial development. To perform global gene expression profiling analysis of mandible and maxilla development and integrate these datasets with cell lineage and quantitative 3D dynamic imaging analyses. In collaboration with the ontology group within the FaceBase consortium, we will define anatomical landmarks and morphometric parameters of the developing mandible and maxilla.
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Project description:Craniofacial development requires intricate cooperation of multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the function of Six1 in mandible development using a Six1 knockout mouse model (Six1-/-) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1f/f; Wnt1-Cre). The Six1-/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Importantly, the Six1f/f; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1-/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and the Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonal skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in the regulation of mandibular skeleton formation during mouse embryogenesis.
2023-03-10 | GSE216759 | GEO
Project description:Craniofacial development requires intricate cooperation of multiple transcription factors and signaling pathways. Six1 is a critical transcription factor regulating craniofacial development. However, the exact function of Six1 during craniofacial development remains elusive. In this study, we investigated the function of Six1 in mandible development using a Six1 knockout mouse model (Six1-/-) and a cranial neural crest-specific, Six1 conditional knockout mouse model (Six1f/f; Wnt1-Cre). The Six1-/- mice exhibited multiple craniofacial deformities, including severe microsomia, high-arched palate, and uvula deformity. Importantly, the Six1f/f; Wnt1-Cre mice recapitulate the microsomia phenotype of Six1-/- mice, thus demonstrating that the expression of Six1 in ectomesenchyme is critical for mandible development. We further showed that the knockout of Six1 led to abnormal expression of osteogenic genes within the mandible. Moreover, the knockdown of Six1 in C3H10 T1/2 cells reduced their osteogenic capacity in vitro. Using RNA-seq, we showed that both the loss of Six1 in the E18.5 mandible and the Six1 knockdown in C3H10 T1/2 led to the dysregulation of genes involved in embryonal skeletal development. In particular, we showed that Six1 binds to the promoter of Bmp4, Fat4, Fgf18, and Fgfr2, and promotes their transcription. Collectively, our results suggest that Six1 plays a critical role in the regulation of mandibular skeleton formation during mouse embryogenesis.
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Project description:Kids First Study in Craniofacial Microsomia: Genetic Causes and Pathway Discovery
| PRJNA671372 | ENA
Project description:Kids First Study in Craniofacial Microsomia: Genetic Causes and Pathway Discovery
| PRJNA671373 | ENA
Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.
2024-03-04 | GSE226184 | GEO
Project description:Certain bone graft materials are employed for alveolar bone regeneration, and autografts are commonly used. Alveolar and jaw bones are developmentally derived from neural crest cells, while most trunk and limb bones are derived from mesodermal mesenchymal cells. Consequently, the chosen bone graft material is likely to have a different developmental origin than the recipient bone. We hypothesized that there are differences in the gene expression profiles and bone healing capacities between bones with different developmental origins. Therefore, we investigated these properties in the maxilla, mandible, ilium and femur. DNA microarray data revealed close homology between the gene expression profiles of the ilium and femur. The gene expressions of Wnt-1, P75, SOX10, Nestin and Musashi-1 were significantly higher in the maxilla and mandible than in the ilium and femur. The frontal bone healed faster than the parietal bone. Parietal bone defects transplanted with maxillary and mandibular bone grafts exhibited closure. Thus, it is suggested that the maxilla and mandible have different gene expression profiles from the other bones examined, and exhibit neural crest cell properties with a marked healing ability in adults. The data further suggest that jaw bones are effective as both bone graft materials and graft beds.
2011-06-30 | GSE30167 | GEO
Project description:The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource).
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</div><div>All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed.
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</div><div>Craniofacial microsomia (CFM), also termed hemifacial microsomia or oculo-auricular-vertebral spectrum, is the third most common congenital craniofacial condition. CFM comprises a variable phenotype and the most common features include malformations of the ear (i.e. microtia) and lower jaw (i.e. mandibular hypoplasia) on one or both sides. Microtia in the absence of other anomalies is believed to represent the mildest form of CFM. The cause of CFM is unknown for most affected individuals. We have established a cohort through previous studies and collected DNA to identify the genetic contributions to CFM, which could facilitate diagnosis, tailored treatments and guide prevention strategies. Successful completion of this proposal will advance knowledge in the genetic architecture of susceptibility to CFM and will provide insight about the biological mechanisms underlying craniofacial development. The results from this study have the potential to further research on the etiology of other craniofacial conditions, and the pathogenesis of typical and atypical craniofacial development.
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| phs002130 | dbGaP
Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA-sequencing reveals that loss of Tet2/3 impaired chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides novel insights into understanding craniofacial development and CFM pathogenesis.
2024-02-02 | PXD049147 | iProX