title: Mind bomb 1 is required for pancreatic β-cell formation.
abstract: 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.
authors.affiliation: Department of Developmental Biology,  Hagedorn Research Institute, DK-2820 Gentofte,  Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Horn
authors.forename: Sune
authors.initials: S
authors.lastname: Kobberup
authors.forename: Mette C
authors.initials: MC
authors.lastname: Jørgensen
authors.forename: Mark
authors.initials: M
authors.lastname: Kalisz
authors.forename: Tino
authors.initials: T
authors.lastname: Klein
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.forename: Moritz
authors.initials: M
authors.lastname: Gegg
authors.forename: Heiko
authors.initials: H
authors.lastname: Lickert
authors.forename: Jill
authors.initials: J
authors.lastname: Lindner
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
authors.forename: Jonas
authors.initials: J
authors.lastname: Ahnfelt-Rønne
authors.forename: Jan N
authors.initials: JN
authors.lastname: Jensen
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C496503:Foxa2 protein, mouse; C496496:Hnf1b protein, mouse; C486455:Maml1 protein, mouse; C407737:Neurog3 protein, mouse; C491328:Nkx6-1 protein, mouse; C062602:transcription factor PTF1; C470629:MIB1 protein, mouse