Regulation of pancreas development by hedgehog signaling
Abstract
Pancreas organogenesis is regulated by the interaction of distinct signaling pathways that promote or restrict morphogenesis and cell differentiation. Previous work has shown that activin, a TGFβ signaling molecule, permits pancreas development by repressing expression of Sonic hedgehog (Shh), a member of the hedgehog family of signaling molecules that antagonize pancreas development. Here we show that Indian hedgehog (Ihh), another hedgehog family member, and Patched 1 (Ptc1), a receptor and negative regulator of hedgehog activity, are expressed in pancreatic tissue. Targeted inactivation of Ihh in mice allows ectopic branching of ventral pancreatic tissue resulting in an annulus that encircles the duodenum, a phenotype frequently observed in humans suffering from a rare disorder known as annular pancreas. Shh−/−and Shh−/−Ihh+/− mutants have a threefold increase in pancreas mass, and a fourfold increase in pancreatic endocrine cell numbers. In contrast, mutations in Ptc1 reduce pancreas gene expression and impair glucose homeostasis. Thus, islet cell, pancreatic mass and pancreatic morphogenesis are regulated by hedgehog signaling molecules expressed within and adjacent to the embryonic pancreas. Defects in hedgehog signaling may lead to congenital pancreatic malformations and glucose intolerance.
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FGF2 and Activin, secreted by the notochord, lead to expression of pancreatic markers by repressing Shh in pancreatic endoderm.
“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 [16]
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Self-citationActivin receptor patterning of foregut organogenesis
Kim, S. K., Hebrok, M., Li, E., Oh, S. P., Schrewe, H., Harmon, E. B., Lee, J. S., & Melton, D. A. (2000) · Genes & Development · doi:10.1101/gad.14.15.1866 · Cited by 212 · see citing works
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- Authors
- Hebrok, M., Kim, S. K., St-Jacques, B., McMahon, A. P., & Melton, D. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Harvard University 2 Department of Molecular and Cellular Biology, The Biolabs , , 16 Divinity Avenue, Cambridge, MA 02138, USA
- Corresponding author
- Melton, Douglas A.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2000-11-15
- Volume
- 127
- Issue
- 22
- Pages
- 4905-4913
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2140923392
- Cited by
- 412
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 12 · 2023: 4 · 2022: 5 · 2021: 10 · 2020: 11 · 2019: 8 · 2018: 21 · 2017: 15 · 2016: 11 · 2015: 17 · 2014: 15 · 2013: 8 · 2012: 22
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS33642)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- pancreatic development, Hedgehog signaling, Indian hedgehog, Sonic hedgehog, Patched1, annular pancreas, pancreatic morphogenesis, pancreatic endocrine cells, glucose homeostasis, congenital pancreatic anomaly, impaired glucose tolerance, activin, TGF-beta signaling
- MeSH terms
- Patched Receptors, Patched-1 Receptor, Animals, Base Sequence, Cell Count, Humans, Membrane Proteins, Mice, Inbred CBA, Mice, Inbred C57BL, Mutation, Pancreas, Proteins, Receptors, Cell Surface, Signal Transduction, Trans-Activators, DNA Primers, Mice, Knockout, Gene Expression Regulation, Developmental, Intracellular Signaling Peptides and Proteins, Mice, Hedgehog Proteins
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