Mind bomb 1 is required for pancreatic ß-cell formation
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Mind bomb 1 is required for pancreatic ß-cell formation. / 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.
In: Proceedings of the National Academy of Sciences USA (PNAS), Vol. 109, No. 19, 08.05.2012, p. 7356-61.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Mind bomb 1 is required for pancreatic ß-cell formation
AU - Horn, Signe
AU - Kobberup, Sune
AU - Jørgensen, Mette C
AU - Kalisz, Mark
AU - Klein, Tino
AU - Kageyama, Ryoichiro
AU - Gegg, Moritz
AU - Lickert, Heiko
AU - Lindner, Jill
AU - Magnuson, Mark A
AU - Kong, Young-Yun
AU - Serup, Palle
AU - Ahnfelt-Rønne, Jonas
AU - Jensen, Jan N
PY - 2012/5/8
Y1 - 2012/5/8
N2 - 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.
AB - 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.
KW - Animals
KW - Basic Helix-Loop-Helix Transcription Factors
KW - Blotting, Western
KW - Cell Lineage
KW - Embryo, Mammalian
KW - Female
KW - Gene Expression Regulation, Developmental
KW - Hepatocyte Nuclear Factor 1-beta
KW - Hepatocyte Nuclear Factor 3-beta
KW - Homeodomain Proteins
KW - Insulin-Secreting Cells
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Mutation
KW - Nerve Tissue Proteins
KW - Nuclear Proteins
KW - Pancreas
KW - Receptors, Notch
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
KW - Time Factors
KW - Transcription Factors
KW - Ubiquitin-Protein Ligases
U2 - 10.1073/pnas.1203605109
DO - 10.1073/pnas.1203605109
M3 - Journal article
C2 - 22529374
VL - 109
SP - 7356
EP - 7361
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 19
ER -
ID: 42005114