Mind bomb 1 is required for pancreatic [Beta]-cell formation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 19; p. 7356
• Main Authors: Horn, Signe, Kobberup, Sune, Jørgensen, Mette C, Kalisz, Mark, Klein, Tino, Kageyama, Ryoichiro, Gegg, Moritz, Lickert, Heiko, Lindner, Jill, Magnuson, Mark A, Kong, Young-Yun, Serup, Palle, Ahnfelt-Rønne, Jonas, Jensen, Jan N
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 08.05.2012
• Subjects: Cells; Developmental biology; Pancreas
• ISSN: 0027-8424; 1091-6490

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 β-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 β-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of β-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and β-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1+Ptf1a- and Hnf1β+ cells and a corresponding loss of Neurog3+ endocrine progenitors and β-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 β-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 β-cell formation. [PUBLICATION ABSTRACT]