Abstract
Acquisition of the lower jaw (mandible) was evolutionarily important for jawed vertebrates. In humans, syndromic craniofacial malformations often accompany jaw anomalies. The basic helix-loop-helix transcription factor Hand2, which is conserved among jawed vertebrates, is expressed in the neural crest in the mandibular process but not in the maxillary process of the first branchial arch. Here, we provide evidence that Hand2 is sufficient for upper jaw (maxilla)-to-mandible transformation by regulating the expression of homeobox transcription factors in mice. Altered Hand2 expression in the neural crest transformed the maxillae into mandibles with duplicated Meckel’s cartilage, which resulted in an absence of the secondary palate. In Hand2-overexpressing mutants, non-Hox homeobox transcription factors were dysregulated. These results suggest that Hand2 regulates mandibular development through downstream genes of Hand2 and is therefore a major determinant of jaw identity. Hand2 may have influenced the evolutionary acquisition of the mandible and secondary palate.
Highlights
The evolution of vertebrates, which first appeared as gnathostomes, is associated with jaw acquisition, as it allowed a shift from passive to active predation[1]
The neural crest cells (NCCs) in the first branchial arch are devoid of Hox homeobox genes, and Hox gene expression in the first branchial NCCs is incompatible with jaw formation[12]
We show that altered expression of the Hand transcription factors, Hand[1] and Hand[2], in NCCs or the osteochondral progenitors induced the transformation of the upper jaw into a lower jaw, which resulted in a missing secondary palate
Summary
The evolution of vertebrates, which first appeared as gnathostomes (jawed vertebrates), is associated with jaw acquisition, as it allowed a shift from passive to active predation[1]. The upper (maxilla) and lower (mandible) jaws and associated soft tissues are derived from the maxillary and mandibular processes, respectively, of the first branchial arch. Ablation of Hand[2] expression in NCCs of the branchial arches results in hypomorphism of the mandibles and Meckel’s cartilage in mice[9,10,11]. We show that altered expression of the Hand transcription factors, Hand[1] and Hand[2], in NCCs or the osteochondral progenitors induced the transformation of the upper jaw into a lower jaw, which resulted in a missing secondary palate. We identified that Hand[2] was located genetically upstream of non-Hox homeobox transcription factors in the development of the first branchial arch. Modification of the Hand[2] gene may correlate with the evolution of vertebrates
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