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Abstract：
During pancreas development, Neurog3 positive endocrine progenitors are specified by Delta/Notch (D/N) mediated lateral inhibition in the growing ducts. During neurogenesis, genes that determine the transition from the proneural state to neuronal or glial lineages are oscillating before their expression is sustained. Although the basic gene regulatory network is very similar, cycling gene expression in pancreatic development was not investigated yet, and previous simulations of lateral inhibition in pancreas development excluded by design the possibility of oscillations. To explore this possibility, we developed a dynamic model of a growing duct that results in an oscillatory phase before the determination of endocrine progenitors by lateral inhibition. The basic network (D/N + Hes1 + Neurog3) shows scattered, stable Neurog3 expression after displaying transient expression. Furthermore, we included the Hes1 negative feedback as previously discussed in neurogenesis and show the consequences for Neurog3 expression in pancreatic duct development. Interestingly, a weakened HES1 action on the Hes1 promoter allows the coexistence of stable patterning and oscillations. In conclusion, cycling gene expression and lateral inhibition are not mutually exclusive. In this way, we argue for a unified mode of D/N mediated lateral inhibition in neurogenic and pancreatic progenitor specification.
摘要：
在胰腺发育过程中,Neurog3阳性内分泌祖细胞由生长中的导管中的Delta/Notch(D/N)介导的侧向抑制指定。在神经发生期间，决定从神经前状态到神经元或神经胶质谱系的转变的基因在其表达持续之前是振荡的。虽然基本的基因调控网络非常相似，胰腺发育中的循环基因表达尚未研究，和先前对胰腺发育的侧向抑制的模拟，通过设计排除了振荡的可能性。为了探索这种可能性，我们开发了一个生长导管的动态模型，该模型在通过侧向抑制确定内分泌祖细胞之前导致振荡阶段。基本网络（D/N+Hes1+Neurog3）显示分散，显示瞬时表达后稳定的Neurog3表达。此外，我们纳入了先前在神经发生中讨论的Hes1负反馈,并显示了在胰管发育中Neurog3表达的后果.有趣的是,削弱HES1对Hes1启动子的作用允许稳定模式和振荡共存。总之,循环基因表达和侧向抑制不是相互排斥的。这样,我们主张在神经源性和胰腺祖细胞规范中建立统一的D/N介导的侧向抑制模式。
