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The neural crest, a population of multipotent progenitor cells, is a defining feature of vertebrate embryos. Neural crest precursor cells arise at the neural plate border in response to inductive signals, but much remains to be learned about the molecular mechanisms underlying their induction. Here we show that the protooncogene c-Myc is an essential early regulator of neural crest cell formation in Xenopus. c-myc is localized at the neural plate border prior to the expression of early neural crest markers, such as slug. A morpholino-mediated "knockdown" of c-Myc protein results in the absence of neural crest precursor cells and a resultant loss of neural crest derivatives. These effects are not dependent upon changes in cell proliferation or cell death. Instead, our findings reveal an important and unexpected role for c-Myc in the specification of cell fates in the early ectoderm.
Figure 1. c-myc Expression Precedes slug Expression in Neural Crest Precursor Cells(A) Anterior and posterior view of c-myc expression in a stage 14 embryo. Strong expression is seen in the anterior neural fold (anterior) and around the closing blastopore (posterior).(B) Comparison of c-myc and pax6 expression in the anterior neural fold.(C) Northern analysis shows that c-myc is expressed both maternally and zygotically.(D) Temporal comparison of c-myc and slug expression. c-myc expression in neural folds can be detected by mid-gastrula stages (stage 11).(E) Double in situ showing blue cells expressing c-myc alone (white arrowhead) and purple cells coexpressing c-myc and slug (black arrowhead). The domain of c-myc expression is wider than the region that also expresses slug.(F) Overexpression of a dominant-negative Wnt ligand prevents c-myc expression (arrowhead).
Figure 2. c-myc, but Not N-myc, Is Expressed in Premigratory Neural Crest CellsIn situ hybridization was used to compare the temporal and spatial relationship between c-myc and N-myc expression at stages 13 (A), 16 (B), 23 (D), and 27 (C). At premigratory neural crest stages (A and B), only c-myc is expressed in neural crest cells. Expression of N-myc at these stages is restricted to a small number of cells in the presumptive CNS.
Figure 4. c-Myc Depletion Does Not Perturb A/P Patterning(A) Expression of sox10 in migratory cranial neural crest cells ([i], arrows) is absent on the c-Myc-depleted side of the embryo (ii).(B) (i) Expression of sox10 in the ear (arrows) and CNS is unperturbed on the c-Myc-depleted side of embryos (red arrowhead) and remains colinear with expression on the control side (white arrowhead). (ii) Expression of krox20 in migratory neural crest cells is absent on the injected side of the embryo (black arrow), while expression in the CNS is unperturbed. CNS expression remains colinear with the uninjected side.(C) In situ hybridization with a muscle actin probe demonstrates that c-Myc MOs targeted to the mesoderm (ii) do not perturb somite development.(D) RT-PCR analysis in ectodermal explants of embryos injected with neural crest-inducing doses of Wnt and chordin. c-Myc MOs inhibit the expression of the neural crest markers slug, twist, and snail. L32 expression serves as a loading control.
Figure 7. c-Myc Depletion Prevents Formation of Cranial Sensory Ganglia(A) sox10 expression in the glia of the trigeminal, seventh (VII), ninth (IX), and tenth (X) cranial ganglia can be visualized on the control (ii), but not the injected (i), side of c-Myc-depleted embryos. E, the developing eye.(B) n-tubulin expression in the CNS neurons (white arrow) can be seen on both the control (ii) and depleted (i) side of the embryo, but n-tubulin expression in cranial sensory ganglia is seen only on the control side (ii).(C) Loss of placodal six-1 expression on the injected side (arrowhead) of c-Myc-depleted embryos (i). Expanded expression of the neural plate border marker opl (zic1) on the injected side (arrowhead) of c-Myc-depleted embryos (ii) shows that not all border cell fates have been lost in these embryos.
