Department of Medical Neurobiology, IMRIC and ELSC, Hebrew University, Hadassah Medical School, Jerusalem 91120, PO Box 12272, Israel.
Development. 2013 Jun;140(11):2269-79. doi: 10.1242/dev.093294. Epub 2013 Apr 24.
Understanding when and how multipotent progenitors segregate into diverse fates is a key question during embryonic development. The neural crest (NC) is an exemplary model system with which to investigate the dynamics of progenitor cell specification, as it generates a multitude of derivatives. Based on 'in ovo' lineage analysis, we previously suggested an early fate restriction of premigratory trunk NC to generate neural versus melanogenic fates, yet the timing of fate segregation and the underlying mechanisms remained unknown. Analysis of progenitors expressing a Foxd3 reporter reveals that prospective melanoblasts downregulate Foxd3 and have already segregated from neural lineages before emigration. When this downregulation is prevented, late-emigrating avian precursors fail to upregulate the melanogenic markers Mitf and MC/1 and the guidance receptor Ednrb2, generating instead glial cells that express P0 and Fabp. In this context, Foxd3 lies downstream of Snail2 and Sox9, constituting a minimal network upstream of Mitf and Ednrb2 to link melanogenic specification with migration. Consistent with the gain-of-function data in avians, loss of Foxd3 function in mouse NC results in ectopic melanogenesis in the dorsal tube and sensory ganglia. Altogether, Foxd3 is part of a dynamically expressed gene network that is necessary and sufficient to regulate fate decisions in premigratory NC. Their timely downregulation in the dorsal neural tube is thus necessary for the switch between neural and melanocytic phases of NC development.
了解多能祖细胞何时以及如何分离成不同的命运是胚胎发育过程中的一个关键问题。神经嵴（NC）是一个很好的模型系统，可以用来研究祖细胞特化的动力学，因为它产生了多种衍生物。基于“在体”谱系分析，我们之前提出了一个早期命运限制，即迁移前的躯干 NC 产生神经与黑色素生成命运的假说，但命运分离的时间和潜在机制仍不清楚。对表达 Foxd3 报告基因的祖细胞进行分析表明，预期的黑色素祖细胞下调 Foxd3，并在迁移前已经从神经谱系中分离出来。当这种下调被阻止时，晚迁移的禽类前体细胞不能上调黑色素生成标记物 Mitf 和 MC/1 以及导向受体 Ednrb2，而是产生表达 P0 和 Fabp 的神经胶质细胞。在这种情况下，Foxd3 位于 Snail2 和 Sox9 下游，构成了 Mitf 和 Ednrb2 上游的最小网络，将黑色素生成特化与迁移联系起来。与禽类的功能获得数据一致，Foxd3 功能缺失导致小鼠 NC 中背侧管和感觉神经节的异位黑色素生成。总之，Foxd3 是一个动态表达的基因网络的一部分，对于调节迁移前 NC 中的命运决定是必要和充分的。因此，它们在背侧神经管中的及时下调对于 NC 发育的神经和黑色素生成阶段之间的转换是必要的。
