Abstract
Cranial neural crest cells undergo cellular growth, patterning, and differentiation within the branchial arches to form cartilage and bone, resulting in a precise pattern of skeletal elements forming the craniofacial skeleton. However, it is unclear how cranial neural crest cells are regulated to give rise to the different shapes and sizes of the bone and cartilage. Epigenetic regulators are good candidates to be involved in this regulation, since they can exert both broad as well as precise control on pattern formation. Here, we investigated the role of the histone acetyltransferases Kat2a and Kat2b in craniofacial development using TALEN/CRISPR/Cas9 mutagenesis in zebrafish and the Kat2ahat/hat (also called Gcn5) allele in mice. kat2a and kat2b are broadly expressed during embryogenesis within the central nervous system and craniofacial region. Single and double kat2a and kat2b zebrafish mutants have an overall shortening and hypoplastic nature of the cartilage elements and disruption of the posterior ceratobranchial cartilages, likely due to smaller domains of expression of both cartilage- and bone-specific markers, including sox9a and col2a1, and runx2a and runx2b, respectively. Similarly, in mice we observe defects in the craniofacial skeleton, including hypoplastic bone and cartilage and altered expression of Runx2 and cartilage markers (Sox9, Col2a1). In addition, we determined that following the loss of Kat2a activity, overall histone 3 lysine 9 (H3K9) acetylation, the main epigenetic target of Kat2a/Kat2b, was decreased. These results suggest that Kat2a and Kat2b are required for growth and differentiation of craniofacial cartilage and bone in both zebrafish and mice by regulating H3K9 acetylation.
Highlights
Craniofacial bones and cartilage of the head and neck must undergo proper differentiation to form specific skeletal elements in adult vertebrates
These results suggest that kat2a and kat2b is required for cartilage and bone differentiation in zebrafish
Kat2b mice have not been reported to have a craniofacial defect, here we show that both Kat2a and Kat2b are required for zebrafish craniofacial development, and the phenotype increases in severity in double Kat2a/2b mutants
Summary
Craniofacial bones and cartilage of the head and neck must undergo proper differentiation to form specific skeletal elements in adult vertebrates. Intramembranous ossification occurs when mesenchymal stem cell precursors directly differentiate into osteoblasts and form the mineralized bone matrix [19,27,28] This process generates the zebrafish craniofacial bones, including the opercle, parasphenoid, branchiostegal rays, cleithrum, mandible, maxilla, and dermal plates of the skull. We observed defects in the neural crest cell-derived craniofacial cartilage and bone formed from both endochondral and intramembranous ossification, including hypoplastic cartilage and bone development in both zebrafish and mice. We observed differential expression of neural crest cell-specific cartilage and bone differentiation factors, including sox9a, col2a1, and runx2a/2b, as well as a reduction in H3K9ac levels in zebrafish and mouse mutant embryos. Our study reveals previously unidentified roles for the histone acetyltransferases kat2a and kat2b in craniofacial development
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