Activin receptor patterning of foregut organogenesis
- Seung K. Kim1,7,8,
- Matthias Hebrok2,6,7,
- En Li3,
- S. Paul Oh4,
- Heinrich Schrewe5,
- Erin B. Harmon1,
- Joon S. Lee1, and
- Douglas A. Melton2,8
- 1Department of Developmental Biology, Stanford University, Stanford, California 94305-5329 USA; 2Howard Hughes Medical Institute and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138 USA; 3Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129 USA; 4Department of Physiology, University of Florida, Gainesville, Florida 32610 USA; 5Department of Developmental Biology, Max-Planck-Institut für Immunbiologie, 79108 Freiburg, Germany; 6Diabetes Research Center, Department of Medicine, University of California, San Francisco, California 94143-0573 USA
Abstract
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 includingShh 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.
