Abstract
The neural crest is a population of multipotent cells that migrates extensively throughout vertebrate embryos to form diverse structures. Mice mutant for the de novo DNA methyltransferase DNMT3b exhibit defects in two neural crest derivatives, the craniofacial skeleton and cardiac ventricular septum, suggesting that DNMT3b activity is necessary for neural crest development. Nevertheless, the requirement for DNMT3b specifically in neural crest cells, as opposed to interacting cell types, has not been determined. Using a conditional DNMT3b allele crossed to the neural crest cre drivers Wnt1-cre and Sox10-cre, neural crest DNMT3b mutants were generated. In both neural crest-specific and fully DNMT3b-mutant embryos, cranial neural crest cells exhibited only subtle migration defects, with increased numbers of dispersed cells trailing organized streams in the head. In spite of this, the resulting cranial ganglia, craniofacial skeleton, and heart developed normally when neural crest cells lacked DNMT3b. This indicates that DNTM3b is not necessary in cranial neural crest cells for their development. We conclude that defects in neural crest derivatives in DNMT3b mutant mice reflect a requirement for DNMT3b in lineages such as the branchial arch mesendoderm or the cardiac mesoderm that interact with neural crest cells during formation of these structures.
Highlights
During early development, cell lineages are determined by the cell type-specific activation of differentiation programs, with concomitant repression of unexpressed developmental pathways.To shut down alternate paths, developmental gene expression is silenced through epigenetics [1,2]
While it is known that the neural plate and dorsal spinal cord express DNMT3b [13,14,15], and that DNMT3b is upregulated as a consequence of neural crest induction [19], the DNMT3b expression pattern in neural crest cells has not been determined
DNMT3b is abundant in the neural plate, including in Sox10-positive neural crest cells in the neural folds (A; arrowheads)
Summary
Cell lineages are determined by the cell type-specific activation of differentiation programs, with concomitant repression of unexpressed developmental pathways.To shut down alternate paths, developmental gene expression is silenced through epigenetics [1,2]. Cell lineages are determined by the cell type-specific activation of differentiation programs, with concomitant repression of unexpressed developmental pathways. Repressive parental DNA methylation is removed or lost, giving the pluripotent cells of the early embryo the capacity to express genes associated with any cell type as inductive signals are received [3]. New epigenetic marks, including methylation of histones and DNA, are laid down on promoters to silence gene expression inappropriate for that time and place in the embryo, gradually ‘‘locking in’’ cell fate decisions and restricting developmental potential [2,4]. A key factor in understanding development, and tackling developmental pathways gone awry (as in cancer), is to define the mechanisms that impose epigenetic marks in developmental lineages
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