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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)
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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
Quellenangaben Band: 109, Heft: 19, Seiten: 7356-7361 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Begutachtungsstatus Peer reviewed