A nonneural epithelial domain of embryonic cranial neural folds gives rise to ectomesenchyme

The neural crest is generally believed to be the embryonic source of skeletogenic mesenchyme (ectomesenchyme) in the vertebrate head and other derivatives, including pigment cells and neurons and glia of the peripheral nervous system. Although classical transplantation experiments leading to this conclusion assumed that embryonic neural folds were homogeneous epithelia, we reported that embryonic cranial neural folds contain spatially and phenotypically distinct domains, including a lateral nonneural domain with cells that coexpress E-cadherin and PDGFRα and a thickened mediodorsal neuroepithelial domain where these proteins are reduced or absent. We now show that Wnt1-Cre is expressed in the lateral nonneural epithelium of rostral neural folds and that cells coexpressing Cre-recombinase and PDGFRα delaminate precociously from some of this nonneural epithelium. We also show that ectomesenchymal cells exhibit β-galactosidase activity in embryos heterozygous for an Ecad-lacZ reporter knock- in allele. We conclude that a lateral nonneural domain of the neural fold epithelium, which we call “metablast,” is a source of ectomesenchyme distinct from the neural crest. We suggest that closer analysis of the origin of ectomesenchyme might help to understand (i ) the molecular-genetic regulation of development of both neural crest and ectomesenchyme lineages; (ii ) the early developmental origin of skeletogenic and connective tissue mesenchyme in the vertebrate head; and (iii ) the presumed origin of head and branchial arch skeletal and connective tissue structures during vertebrate evolution.