Mind bomb 1 is required for pancreatic ß-cell formation

Signe Horn; Sune Kobberup; Mette C Jørgensen; Mark Kalisz; Tino Klein; Ryoichiro Kageyama; Moritz Gegg; Heiko Lickert; Jill Lindner; Mark A Magnuson; Young-Yun Kong; Palle Serup; Jonas Ahnfelt-Rønne; Jan N Jensen

doi:10.1073/pnas.1203605109

Mind bomb 1 is required for pancreatic ß-cell formation

Signe Horn, Sune Kobberup, Mette C Jørgensen, Mark Kalisz, Tino Klein, Ryoichiro Kageyama, Moritz Gegg, Heiko Lickert, Jill Lindner, Mark A Magnuson, Young-Yun Kong, Palle Serup, Jonas Ahnfelt-Rønne, Jan N Jensen

Developmental biology of the pancreas Lab

54 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences USA (PNAS)
Volume	109
Issue number	19
Pages (from-to)	7356-61
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1203605109
Publication status	Published - 8 May 2012

Keywords

Animals
Basic Helix-Loop-Helix Transcription Factors
Blotting, Western
Cell Lineage
Embryo, Mammalian
Female
Gene Expression Regulation, Developmental
Hepatocyte Nuclear Factor 1-beta
Hepatocyte Nuclear Factor 3-beta
Homeodomain Proteins
Insulin-Secreting Cells
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mutation
Nerve Tissue Proteins
Nuclear Proteins
Pancreas
Receptors, Notch
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Time Factors
Transcription Factors
Ubiquitin-Protein Ligases

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10.1073/pnas.1203605109

http://www.pnas.org/content/109/19/7356.short

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Horn, S., Kobberup, S., Jørgensen, M. C., Kalisz, M., Klein, T., Kageyama, R., Gegg, M., Lickert, H., Lindner, J., Magnuson, M. A., Kong, Y.-Y., Serup, P., Ahnfelt-Rønne, J., & Jensen, J. N. (2012). Mind bomb 1 is required for pancreatic ß-cell formation. Proceedings of the National Academy of Sciences USA (PNAS), 109(19), 7356-61. https://doi.org/10.1073/pnas.1203605109

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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.",

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author = "Signe Horn and Sune Kobberup and J{\o}rgensen, {Mette C} and Mark Kalisz and Tino Klein and Ryoichiro Kageyama and Moritz Gegg and Heiko Lickert and Jill Lindner and Magnuson, {Mark A} and Young-Yun Kong and Palle Serup and Jonas Ahnfelt-R{\o}nne and Jensen, {Jan N}",

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doi = "10.1073/pnas.1203605109",

language = "English",

volume = "109",

pages = "7356--61",

journal = "Proceedings of the National Academy of Sciences USA (PNAS)",

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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 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.

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 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.

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

SN - 0027-8424

VL - 109

SP - 7356

EP - 7361

JO - Proceedings of the National Academy of Sciences USA (PNAS)

JF - Proceedings of the National Academy of Sciences USA (PNAS)

IS - 19

ER -

Mind bomb 1 is required for pancreatic ß-cell formation

Abstract

Keywords

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