Thomas Aaron J, Erickson Carol A
Molecular and Cellular Biology, University of California Davis, Davis, CA 95616, USA.
Development. 2009 Jun;136(11):1849-58. doi: 10.1242/dev.031989. Epub 2009 Apr 29.
The first neural crest cells to emigrate from the neural tube are specified as neurons and glial cells and are subsequently followed by melanocytes of the skin. We wished to understand how this fate switch is controlled. The transcriptional repressor FOXD3 is expressed exclusively in the neural/glial precursors and MITF is expressed only in melanoblasts. Moreover, FOXD3 represses melanogenesis. Here we show that avian MITF expression begins very early during melanoblast migration and that loss of MITF in melanoblasts causes them to transdifferentiate to a glial phenotype. Ectopic expression of FOXD3 represses MITF in cultured neural crest cells and in B16-F10 melanoma cells. We also show that FOXD3 does not bind directly to the MITF promoter, but instead interacts with the transcriptional activator PAX3 to prevent the binding of PAX3 to the MITF promoter. Overexpression of PAX3 is sufficient to rescue MITF expression from FOXD3-mediated repression. We conclude that FOXD3 controls the lineage choice between neural/glial and pigment cells by repressing MITF during the early phase of neural crest migration.
首批从神经管迁移出来的神经嵴细胞被指定为神经元和神经胶质细胞，随后是皮肤黑素细胞。我们希望了解这种命运转换是如何被控制的。转录抑制因子FOXD3仅在神经/神经胶质前体细胞中表达，而MITF仅在成黑素细胞中表达。此外，FOXD3抑制黑色素生成。在此我们表明，禽类MITF的表达在成黑素细胞迁移过程中很早就开始了，而成黑素细胞中MITF的缺失会导致它们转分化为神经胶质表型。在培养的神经嵴细胞和B16-F10黑色素瘤细胞中，FOXD3的异位表达会抑制MITF。我们还表明，FOXD3并不直接与MITF启动子结合，而是与转录激活因子PAX3相互作用，以阻止PAX3与MITF启动子结合。PAX3的过表达足以从FOXD3介导的抑制中挽救MITF的表达。我们得出结论，FOXD3通过在神经嵴迁移的早期阶段抑制MITF来控制神经/神经胶质细胞和色素细胞之间的谱系选择。
