Signals from the neural crest regulate beta-cell mass in the pancreas.
ABSTRACT Pancreatic islet cells and neurons share common functions and similar ontogenies, but originate in different germ layers. To determine whether ectoderm-derived cells contribute instructive signals to the developing endoderm-derived pancreas, we defined the chronology of migration and differentiation of neural crest cells in the pancreas, and tested their role in the development of the islets. The homeodomain transcription factor Phox2b marks the neural precursors from the neural crest that colonize the gut to form the enteric nervous system. In the embryonic mouse pancreas, we found Phox2b expressed briefly together with Sox10 along the epithelial-mesenchymal border at E12.5 in cells derived from the neural crest. Downregulation of Phox2b shortly thereafter was dependent upon Nkx2.2 expressed in the adjacent pancreatic epithelium. In Phox2b(-/-) embryos, neurons and glia did not develop in the pancreas, and Nkx2.2 expression was markedly upregulated in the epithelium. In addition, the number and replication rate of insulin-expressing beta-cells increased in the Phox2b(-/-) mice. We conclude that, during pancreatic development, Phox2b and Nkx2.2 form a non-cell-autonomous feedback loop that links the neural crest with the pancreatic epithelium, regulates the size of the beta-cell population, and thereby impacts insulin-secretory capacity and energy homeostasis.
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ABSTRACT: Despite intensive research, a treatment for diabetic patients that completely restores normoglycemia for an indefinite period of time remains elusive. Although islet transplantation temporarily confers normoglycemia to patients, the lack of a renewable source of insulin-producing β cells hampers the use of this treatment option. Although significant hurdles remain, recent advances in stem cell biology indicate that generation of fully matured β cells from uncommitted progenitor cells, including human embryonic stem cells and induced pluripotent stem cells derived from somatic cell populations, is becoming an achievable goal.Cold Spring Harbor Perspectives in Medicine 06/2012; 2(6):a007674. DOI:10.1101/cshperspect.a007674
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ABSTRACT: Interactions between cells from the ectoderm and mesoderm influence development of the endodermally-derived pancreas. While much is known about how mesoderm regulates pancreatic development, relatively little is understood about how and when the ectodermally-derived neural crest regulates pancreatic development and specifically, beta cell maturation. A previous study demonstrated that signals from the neural crest regulate beta cell proliferation and ultimately, beta cell mass. Here, we expand on that work to describe timing of neural crest arrival at the developing pancreatic bud and extend our knowledge of the non-cell autonomous role for neural crest derivatives in the process of beta cell maturation. We demonstrated that murine neural crest entered the pancreatic mesenchyme between the 26 and 27 somite stages (approximately 10.0 dpc) and became intermingled with pancreatic progenitors as the epithelium branched into the surrounding mesenchyme. Using a neural crest-specific deletion of the Forkhead transcription factor Foxd3, we ablated neural crest cells that migrate to the pancreatic primordium. Consistent with previous data, in the absence of Foxd3, and therefore the absence of neural crest cells, proliferation of insulin-expressing cells and insulin-positive area are increased. Analysis of endocrine cell gene expression in the absence of neural crest demonstrated that, although the number of insulin-expressing cells was increased, beta cell maturation was significantly impaired. Decreased MafA and Pdx1 expression illustrated the defect in beta cell maturation; we discovered that without neural crest, there was a reduction in the percentage of insulin-positive cells that co-expressed Glut2 and Pdx1 compared to controls. In addition, transmission electron microscopy analyses revealed decreased numbers of characteristic insulin granules and the presence of abnormal granules in insulin-expressing cells from mutant embryos. Together, these data demonstrate that the neural crest is a critical regulator of beta cell development on two levels: by negatively regulating beta cell proliferation and by promoting beta cell maturation.Developmental Biology 11/2010; 349(2):321-30. DOI:10.1016/j.ydbio.2010.11.013