Tiedemann Hendrik B, Schneltzer Elida, Beckers Johannes, Przemeck Gerhard K H, Hrabě de Angelis Martin
Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Sciences Weihenstephan, Technische Universität München, Alte Akademie 8, 85354 Freising, Germany.
J Theor Biol. 2017 Oct 7;430:32-44. doi: 10.1016/j.jtbi.2017.06.006. Epub 2017 Jun 23.
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.
在胰腺发育过程中，Neurog3阳性内分泌祖细胞是由生长中的导管中Delta/Notch（D/N）介导的侧向抑制作用所特化的。在神经发生过程中，决定从神经前体细胞状态向神经元或神经胶质谱系转变的基因在其表达持续之前会发生振荡。尽管基本的基因调控网络非常相似，但胰腺发育过程中循环基因表达尚未得到研究，并且之前胰腺发育中侧向抑制的模拟在设计上排除了振荡的可能性。为了探索这种可能性，我们建立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会产生一个振荡阶段。基本网络（D/N + Hes1 + Neurog3）在短暂表达后显示出分散、稳定的Neurog3表达。此外，我们纳入了如之前在神经发生中所讨论的Hes1负反馈，并展示了其对胰腺导管发育中Neurog3表达的影响。有趣的是，HES1对Hes1启动子作用的减弱使得稳定模式和振荡能够共存。总之，循环基因表达和侧向抑制并非相互排斥。通过这种方式，我们主张在神经源性和胰腺祖细胞特化过程中，D/N介导的侧向抑制存在统一模式。
