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 -