Mind bomb 1 is required for pancreatic β-cell formation
Mind bomb 1 is required for pancreatic β-cell formation
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DOI：
10.1073/pnas.1203605109
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发表时间：
2012-05-08
影响因子：
11.1
通讯作者：
Jensen, Jan N.
中科院分区：
文献类型：
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作者：
Horn, Signe;Kobberup, Sune;Jensen, Jan N.
在早期胰腺发育过程中，Notch信号抑制内分泌细胞的分化并促进Nkx 6 -1（+）Ptf 1a（+）多能祖细胞（MPC）的增殖。后来，Nkx 6转录因子和Ptf 1a之间的拮抗性相互作用将MPC分离为远端Nkx 6 -1（-）Ptf 1a（+）腺泡祖细胞和近端Nkx 6 -1（+）Ptf 1a（-）导管和β细胞祖细胞。远端细胞最初是多能的，但演变成单能的腺泡细胞祖细胞。相反，近端细胞是双能的，并产生导管细胞和晚生内分泌细胞，包括产生胰岛素的β细胞。然而，调节近远侧（P-D）图案化并因此形成β-细胞祖细胞的信号是未知的。在这里，我们表明，思维炸弹1（Mib 1）是正确的P-D模式的发展胰腺和β细胞形成所必需的。我们发现，Mib 1的内胚层特异性失活导致Nkx 6 -1（+）Ptf 1a（-）和Hnf 1 β（+）细胞的损失以及Neurog 3（+）内分泌祖细胞和β细胞的相应损失。伴随着Nkx 6 -1（-）Ptf 1a（+）和淀粉酶（+）细胞的增加，占据近端结构域，表明近端细胞在Mib 1活性缺乏的情况下采取远端命运。通过显性负性Mastermind-like 1（Maml 1）的条件表达阻碍Notch介导的转录激活导致类似的扭曲的P-D模式和抑制的β细胞形成，Notch靶基因Hes 1的条件失活也是如此。我们的研究结果揭示了在胰腺发育中反复使用Notch以确保正确的P-D模式和足够的β细胞形成。
During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1(+)Ptf1a(+) multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1(-)Ptf1a(+) acinar progenitors and proximal Nkx6-1(+)Ptf1a(-) duct and beta-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing beta-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of beta-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and beta-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1 beta(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and beta-cells. An accompanying increase in Nkx6-1(-)Ptf1a(+) and amylase(+) cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed beta-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate beta-cell formation.