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Activin receptor patterning of foregut organogenesis
Open accessAbstract
Foregut development produces a characteristic sequence of gastrointestinal and respiratory organs, but the signaling pathways that ensure this developmental order remain largely unknown. Here, mutations of activin receptors ActRIIA and ActRIIB are shown to disrupt the development of posterior foregut-derived organs, including the stomach, pancreas, and spleen. Foregut expression of genes including Shh and Isl1 is shifted in mutant mice. The endocrine pancreas is particularly sensitive to the type and extent of receptor inactivation. ActRIIA+/−B+/−animals lack axial defects, but have hypoplastic pancreatic islets, hypoinsulinemia, and impaired glucose tolerance. Thus, activin receptor-mediated signaling regulates axial patterning, cell differentiation, and function of foregut-derived organs.
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“FGF2 and Activin, secreted by the notochord, lead to the expression of pancreatic markers by repressing expression of Shh in pancreatic endoderm [15-19].”
From A systematic screen for genes expressed in definitive endoderm by Serial Analysis of Gene Expression (SAGE) (2007) · cites this paper as [17]
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Self-citationActivin A in Mammalian Physiology
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COUP-TFIIis essential for radial and anteroposterior patterning of the stomach
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“Activin A, a member of the transforming growth factor(TGF- ) superfamily, regulates growth and differentiation of many types of cells (16) and also regulates pancreatic development and endocrine determination (17,18).”
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Self-citationStomach regional specification requiresHoxa5-driven mesenchymal-epithelial signaling
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Hedgehog signaling pathway is essential for pancreas specification in the zebrafish embryo
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Requirement for the L-type Ca2+ channel α1D subunit in postnatal pancreatic β cell generation
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BackgroundInfluentialActivin B receptor ALK7 is a negative regulator of pancreatic β-cell function
Bertolino, P., Holmberg, R., Reissmann, E., Andersson, O., Berggren, P., & Ibáñez, C. F. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801285105 · Cited by 94
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“Activin receptor II inactivation in the mouse reveals a requirement for these receptors in A-P patterning in the foregut (Kim et al., 2000).”
BackgroundFeingold syndrome: Clinical review and genetic mapping
Celli, J., van Bokhoven, H., & Brunner, H. G. (2003) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.20471 · Cited by 82
“Defects in the genes encoding the downstream effectors of sonic hedgehog also cause a number of similar abnormalities [Motoyama et al., 1998; Kim et al., 2000; Mahlapuu et al., 2001].”
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“The activin-activin receptor-follistatin signaling pathway has been shown to be essential in organ developmentspecifically, digit formation (22), foregut formation (23, 24), and tooth development (2529).”
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Herrera, P., Népote, V., & Delacour, A. (2002) · Endocrine · doi:10.1385/endo:19:3:267 · Cited by 68
Zhong, X., Pons, M., Poirier, C., Jiang, Y., Liu, J., Sandusky, G. E., Shahda, S., Nakeeb, A., Schmidt, C. M., House, M. G., et al. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12461 · Cited by 74
Mechanisms of embryonic stomach development
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“Reduction in Activin receptor signaling leads to similar gastric phenotypes as observed in Raldh2 mutants [32], but the TGFβ pathway has not been more thoroughly investigated for its role in stomach development.”
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Progenitor cells in the adult pancreas
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Hedgehog Signaling in the Normal and Diseased Pancreas
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“These data have been confirmed in activin receptor II AB mice that exhibit severe pancreatic defects, reduced pancreatic primordia, and Shh misexpression.(27) Indian hedgehog (Ihh) is localized and expressed in the mouse gut endoderm from the hind stomach to the anus (except in the pancreatic buds) for up to 14.”
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“…type IIA receptor) indicates that Activin receptors function to regulate pancreas and islet size, but not endocrine lineage specification, since ActR mutant mice show pancreatic and islet hypoplasia, with no change in endocrine cell ratio (Andersson et al., 2006; Kim et al., 2000; Oh et al., 2002).”
BackgroundIncreased Muscle Force Production and Bone Mineral Density in ActRIIB-Fc-Treated Mature Rodents
Chiu, C.-S., Peekhaus, N., Weber, H., Adamski, S., Murray, E. M., Zhang, H. Z., Zhao, J. Z., Ernst, R., Lineberger, J., Huang, L., et al. (2013) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glt030 · Cited by 68
“At necropsy, histology was performed to determine muscle mass, femoral BMD, and the spleen weight (28).”
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Emerging roles for the TGFβ family in pancreatic β-cell homeostasis
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Dichmann, D. S., Yassin, H., & Serup, P. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20953 · Cited by 62
“…growth factor-beta (TGF ) superfamily have been shown to influence pancreas development and several genes encoding TGF ligands as well as their receptors and antagonists are expressed during pancreas ontogeny (Lyons et al., 1995; Miralles et al., 1998a,b; Kim et al., 2000; Dichmann et al., 2003).”
BackgroundInfluentialTulachan, S., Tei, E., Hembree, M. J., Crisera, C. A., Prasadan, K. L., Koizumi, M., Shah, S. R., Guo, P., Böttinger, E. P., & Gittes, G. K. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.02.033 · Cited by 61
Promotion of β-Cell Differentiation by Conophylline in Fetal and Neonatal Rat Pancreas
Ogata, T., Li, L., Yamada, S., Yamamoto, Y., Tanaka, Y., Takei, I., Umezawa, K., & Kojima, I. (2004) · Diabetes · doi:10.2337/diabetes.53.10.2596 · Cited by 61
Molecular pathways controlling pancreas induction
McCracken, K. W., & Wells, J. M. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.06.009 · Cited by 59
“In vivo, mouse embryos with compound mutations in the activin receptor subunits (ActRIIA+/−B−/−) have ectopic Shh expression in the Pdx1 domain and a reduction in pancreatic markers including Islet1 (Kim et al., 2000).”
BackgroundSchwitzgebel, V. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00628-1 · Cited by 59
Zhang, Y.-Q., Cleary, M. M., Si, Y., Liu, G., Eto, Y., Kritzik, M. R., Dabernat, S., Kayali, A. G., & Sarvetnick, N. (2004) · Diabetes · doi:10.2337/diabetes.53.8.2024 · Cited by 59
Development and diseases of the pancreas
Johansson, K., & Grapin‐Botton, A. (2002) · Clinical Genetics · doi:10.1034/j.1399-0004.2002.620102.x · Cited by 57
Hou, J., Charters, A. M., Lee, S. C., Zhao, Y., Wu, M. K., Jones, S. J., Marra, M. A., & Hoodless, P. A. (2007) · BMC Developmental Biology · doi:10.1186/1471-213x-7-92 · Cited by 56
“FGF2 and Activin, secreted by the notochord, lead to the expression of pancreatic markers by repressing expression of Shh in pancreatic endoderm [15-19].”
BackgroundALK7, a Receptor for Nodal, Is Dispensable for Embryogenesis and Left-Right Patterning in the Mouse
Jörnvall, H., Reissmann, E., Andersson, O., Mehrkash, M., & Ibáñez, C. F. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.21.9383-9389.2004 · Cited by 55
“dition, no signs of spleen hypoplasia, a phenotype found in compound ActRIIA ActRIIB mutant mice (11), could be detected in ALK7 / mice (Fig.”
BackgroundReciprocal modulation of adult beta cell maturity by activin A and follistatin
Szabat, M., Johnson, J. D., & Piret, J. M. (2010) · Diabetologia · doi:10.1007/s00125-010-1758-0 · Cited by 56
“Activins control embryonic patterning of foregut-derived organs [19], have important roles in pancreatic development [20] and have been implicated in the control of insulin secretion [21, 22].”
BackgroundPancreatic tissue formation from murine embryonic stem cells in vitro
Nakanishi, M., Hamazaki, T. S., Komazaki, S., Okochi, H., & Asashima, M. (2006) · Differentiation · doi:10.1111/j.1432-0436.2006.00109.x · Cited by 53
“Some reports have also suggested that differentiation into pancreatic endocrine cells is regulated by TGF-b signal transduction mediated via activin receptors (Sanvito et al., 1994; Ritvos et al., 1995; Miralles et al., 1998; Yamaoka et al., 1998; Shiozaki et al., 1999; Kim et al., 2000).”
BackgroundA Stem Cell Approach to Cure Type 1 DiabetesPreprint
Helman, A., & Melton, D. A. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035741 · Cited by 56
Self-citationConditional Activin Receptor Type 1B (Acvr1b) Knockout Mice Reveal Hair Loss Abnormality
Qiu, W., Li, X., Tang, H., Huang, A. S., Panteleyev, A. A., Owens, D. M., & Su, G. H. (2010) · Journal of Investigative Dermatology · doi:10.1038/jid.2010.400 · Cited by 52
“…organs (Smith et al., 1990; Thomsen et al., 1990; Mathews et al., 1992; Hubner et al., 1997; Gu et al., 1998; Woodruff, 1998; Song et al., 1999; Kim et al., 2000; Ball and Risbridger, 2001; Chen et al., 2004; Thompson et al., 2004), and tumor suppression (Matzuk et al., 1992; Su et al., 2001;…”
(Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives
Baeyens, L., Lemper, M., Staels, W., Groef, S. D., Leu, N. D., Heremans, Y., German, M. S., & Heimberg, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2016 · Cited by 52
Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells
El‐Gohary, Y., Wiersch, J. C., Tulachan, S., Xiao, X., Guo, P., Rymer, C., Fischbach, S., Prasadan, K. L., Shiota, C., Gaffar, I. M., et al. (2015) · Endocrinology · doi:10.1210/en.2015-1175 · Cited by 52
Smad signaling pathways regulate pancreatic endocrine development
El‐Gohary, Y., Tulachan, S., Guo, P., Welsh, C., Wiersch, J. C., Prasadan, K. L., Paredes, J. L., Shiota, C., Xiao, X., Wada, Y., et al. (2013) · Developmental Biology · doi:10.1016/j.ydbio.2013.04.003 · Cited by 51
“TGF-β superfamily signaling has been shown to play an important role in regulating many developmental and physiologic processes in the pancreas and in the β-cell (Goto et al., 2007; Harmon et al., 2004; Kim et al., 2000; Miralles et al., 1998a; Miralles et al., 1998b; Rane et al., 2006; Ritvos et al., 1995; Sanvito et…”
BackgroundPrimary cilia in pancreatic development and disease
Lodh, S., O’Hare, E. A., & Zaghloul, N. A. (2014) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.21063 · Cited by 51
“The repression of Shh in the dorsal pancreatic bud endoderm is mediated by notochordderived signals, namely the TGF-β family member, activin-βB, and FGFs (Kim et al., 1997a; Hebrok et al., 1998; Kim et al., 2000).”
BackgroundInfluentialOn the origin of the β cellPreprint
Oliver-Krasinski, J. M., & Stoffers, D. A. (2008) · Genes & Development · doi:10.1101/gad.1670808 · Cited by 361
“Consistent with the idea that activin signaling is necessary for inhibition of Shh and pancreatic specification, activin receptor II loss of function mouse mutants have decreased pancreatic size with a concomitant misexpression of Shh and reduced Isl1 expression (Kim et al. 2000).”
BackgroundTGF-β Signaling in Pancreatic Islet β Cell Development and Function
Lee, J., Lee, J.-H., & Rane, S. G. (2020) · Endocrinology · doi:10.1210/endocr/bqaa233 · Cited by 51
Self-citationShh-dependent differentiation of intestinal tissue from embryonic pancreas by activin A
van Eyll, J. M., Pierreux, C. E., Lemaigre, F. P., & Rousseau, G. G. (2004) · Journal of Cell Science · doi:10.1242/jcs.01067 · Cited by 48
“The finding that activin A can induce Shh in differentiating pancreas should be taken into account to interpret the phenotype of knockout mouse embryos lacking activin receptors (Kim et al., 2000).”
Skoudy, A., Rovira, M., Savatier, P., Martín, F., León-Quinto, T., Soria, B., & Real, F. (2004) · Biochemical Journal · doi:10.1042/bj20031784 · Cited by 54
Ogihara, T., Watada, H., Kanno, R., Ikeda, F., Nomiyama, T., Tanaka, Y., Nakao, A., German, M. S., Kojima, I., & Kawamori, R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302684200 · Cited by 44
Adhesion Protein VSIG1 Is Required for the Proper Differentiation of Glandular Gastric Epithelia
Oidovsambuu, O., Nyamsuren, G., Liu, S., Göring, W., Engel, W., & Adham, I. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025908 · Cited by 42
“In contrast, embryos with mutations in activin receptor type II (ActR), FGF10 and its receptor FGFR2b develop multilayered squamous epithelia in the corpus of the distal stomach [18,19].”
BackgroundIntracellular and extracellular control of activin function by novel regulatory molecules
Tsuchida, K., Matsuzaki, T., Yamakawa, N., Liu, Z. H., & Sugino, H. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00522-6 · Cited by 42
Developmental Aspects of the Endocrine Pancreas
Kemp, D. M., Thomas, M. K., & Habener, J. F. (2003) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/a:1021809917576 · Cited by 38
Hypoplasia of endocrine and exocrine pancreas in homozygous transgenic TGF-β1
Moritani, M., Yamasaki, S., Kagami, M., Suzuki, T., Yamaoka, T., Sano, T., Hata, J.-I., & Itakura, M. (2005) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2004.08.007 · Cited by 37
“…islet size or exocrine pancreas in is decreased by the decreased TGF- signaling through de fective type II TGF- , type IIA or IIB activin receptors (Kim et al., 2000), or decreased receptor functions by transgeni pression of a dominant negative type I activin (Yamaoka et al 303-7207/$ – see front…”
BackgroundActivin B mediated induction of Pdx1 in human embryonic stem cell derived embryoid bodies
Frandsen, U., Pørneki, A. D., Floridon, C., Abdallah, B. M., & Kassem, M. S. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.07.200 · Cited by 37
Up-Regulation of the Expression of Activins in the Pancreatic Duct by Reduction of the β-Cell Mass
Zhang, Y.-Q., Zhang, H., Maeshima, A., Kurihara, H., Miyagawa, J., Takeuchi, T., & Kojima, I. (2002) · Endocrinology · doi:10.1210/en.2002-220089 · Cited by 37
Nomura, M., Zhu, H.-L., Wang, L., Morinaga, H., Takayanagi, R., & Teramoto, N. (2013) · Diabetologia · doi:10.1007/s00125-013-3062-2 · Cited by 36
“This islet hyperplasia phenotype appears contradictory to previous observations in mice heterozygous for the Smad2 null allele [13, 15].”
BackgroundNeurogenin 3 is a key transcription factor for differentiation of the endocrine pancreas.
Watada, H. (2004) · Endocrine journal · doi:10.1507/endocrj.51.255 · Cited by 35
SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models
Xu, E. E., Krentz, N. A. J., Tan, S. S., Chow, S. Z., Tang, M., Nian, C., & Lynn, F. C. (2015) · Diabetologia · doi:10.1007/s00125-015-3507-x · Cited by 35
“Signals from adjacent tissues support budding and as development proceeds, two waves of differentiation occur [4–8].”
BackgroundImpaired growth of pancreatic exocrine cells in transgenic mice expressing human activin βE subunit
Hashimoto, O., Ushiro, Y., Sekiyama, K., Yamaguchi, O., Yoshioka, K., MUTOH, K.-I., & Hasegawa, Y. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.12.205 · Cited by 33
Organogenesis of the exocrine gland
Wang, J., & Laurie, G. W. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.05.025 · Cited by 34
Metadata
- Authors
- Kim, S. K., Hebrok, M., Li, E., Oh, S. P., Schrewe, H., Harmon, E. B., Lee, J. S., & Melton, D. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-08-01
- Volume
- 14
- Issue
- 15
- Pages
- 1866-1871
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316826
- OpenAlex
- W1768073869
- Cited by
- 212
- References
- 33
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 6 · 2019: 3 · 2018: 9 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- Donald E. and Delia B. Baxter Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- activin receptors, ActRIIA, ActRIIB, pancreatic islets, endocrine pancreas, hypoinsulinemia, glucose tolerance, stomach development, spleen development, Sonic hedgehog, Isl1, axial patterning, mouse mutants
- MeSH terms
- Animals, Cell Differentiation, Digestive System, Digestive System Physiological Phenomena, Glucose Tolerance Test, Hyperplasia, Insulin, Male, Mice, Mutant Strains, Nerve Tissue Proteins, Pancreas, Proteins, Spleen, Stomach, Transcription Factors, Trans-Activators, Receptors, Growth Factor, Homeodomain Proteins, Body Patterning, Activin Receptors, Type II, Mice, Hedgehog Proteins, LIM-Homeodomain Proteins
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