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Horn, S.* ; Kobberup, S.* ; Jorgensen, M.C.* ; Kalisz, M.* ; Klein, T.* ; Kageyama, R.* ; Gegg, M. ; Lickert, H. ; Lindner, J.* ; Magnuson, M.A.* ; Kong, Y.Y.* ; Serup, P.* ; Ahnfelt-Ronne, J.* ; Jensen, J.N.*

Mind bomb 1 is required for pancreatic β-cell formation.

Proc. Natl. Acad. Sci. U.S.A. 109, 7356-7361 (2012)
DOI PMC
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Diabetes ; Lateral Signaling ; Tip ; Trunk; EMBRYONIC STEM-CELLS; E3 UBIQUITIN LIGASE; ENDOCRINE DEVELOPMENT; MIND BOMB-1; NOTCH; DIFFERENTIATION; EXPRESSION; COMPLEX; DELTA; FATE
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 109, Heft: 19, Seiten: 7356-7361 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Regeneration Research (IDR)
Institute of Stem Cell Research (ISF)