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Mind bomb 1 is required for pancreatic ß-cell formation

Publikation: Forskning - peer reviewTidsskriftartikel

Signe Horn, Sune Kobberup, Mette C Jørgensen, Mark Kalisz, Tino Klein, Ryoichiro Kageyama, Moritz Gegg, Heiko Lickert, Jill Lindner, Mark A Magnuson, Young-Yun Kong, Palle Serup, Jonas Ahnfelt-Rønne, Jan N Jensen

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 ß-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 ß-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of ß-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and ß-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1ß(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and ß-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 ß-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 ß-cell formation.
OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences USA (PNAS)
Vol/bind109
Tidsskriftsnummer19
Sider (fra-til)7356-61
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 8 maj 2012

ID: 42005114