Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Genes Dev. 2011 Aug 15;25(16):1680-5. doi: 10.1101/gad.16875711.
Using single transcription factors to reprogram cells could produce important insights into the epigenetic mechanisms that direct normal differentiation, or counter inappropriate plasticity, or even provide new ways of manipulating normal ontogeny in vitro to control lineage diversification and differentiation. We enforced Pdx1 expression from the Neurogenin-3-expressing endocrine commitment point onward and found during the embryonic period a minor increased β-cell allocation with accompanying reduced α-cell numbers. More surprisingly, almost all remaining Pdx1-containing glucagon/Arx-producing cells underwent a fairly rapid conversion at postnatal stages, through glucagon-insulin double positivity, to a state indistinguishable from normal β cells, resulting in complete α-cell absence. This α-to-β conversion was not caused by activating Pdx1 in the later glucagon-expressing state. Our findings reveal that Pdx1 can work single-handedly as a potent context-dependent autonomous reprogramming agent, and suggest a postnatal differentiation evaluation stage involved in normal endocrine maturation.
使用单一转录因子对细胞进行重编程，可以深入了解指导正常分化的表观遗传机制，或者对抗不适当的可塑性，甚至提供新的方法来体外操纵正常的个体发生，以控制谱系多样化和分化。我们从表达神经基因-3的内分泌细胞成熟点开始强制表达 Pdx1，发现在胚胎期β细胞的分配略有增加，同时α细胞数量减少。更令人惊讶的是，在出生后的阶段，几乎所有剩余的含有 Pdx1 的胰高血糖素/Arx 产生细胞都通过胰高血糖素-胰岛素双阳性，快速转变为与正常β细胞无法区分的状态，导致α细胞完全缺失。这种α到β的转化不是由在后期表达胰高血糖素的状态下激活 Pdx1 引起的。我们的发现表明，Pdx1 可以单独作为一种强大的、依赖于上下文的自主重编程因子发挥作用，并提示在正常内分泌成熟过程中涉及到一个出生后的分化评估阶段。
