Similarities in the developmental programs that drive the differentiation of the serotonergic neurons and pancreatic β-cells led us to examine whether the β-cells can also produce serotonin. We found that the β-cells, as well as some other islet cell types, express all of the genes required to synthesize, package, and secrete serotonin. β-Cells express both isoforms of TPH, the enzyme that catalyzes the rate-limiting step in serotonin synthesis: hydroxylation of tryptophan to 5-hydroxytryptophan. Expression of TPH1 peaks in the neonatal period in the islet. In addition, β-cells express dopamine decarboxylase, the enzyme that catalyzes the next (final) step in serotonin synthesis: decarboxylation of 5-hydroxytryptophan to 5-hydroxytryptamine (serotonin). β-Cells also express VMAT2, the transporter that loads serotonin into secretory vesicles. Interestingly, islet cells express very low levels or none of the synapse-related serotonergic genes SLC6A4 and Htr1a.
The expression of dopamine decarboxylase and the VMATs gives islet cells the ability to decarboxylate and store monoamine precursors and thus the APUD phenotype described almost 50 years ago (1
). This capacity to take up and store serotonin has been exploited by using serotonin as a surrogate for insulin secretion (42
) and by using ligands of VMAT2 for imaging β-cell mass in vivo (43
). Monoamine uptake and storage are characteristics shared by many neuroendocrine cells, but since the islet cells also have TPH activity, they can specifically synthesize, store, and secrete serotonin.
The peak in Tph1
expression in islets that occurs during the perinatal period may provide one explanation for the variability in islet serotonin content seen in prior studies. We and others have also found that islet serotonin content is higher in females and during pregnancy (44
). This variability in serotonin production by islets demonstrates a form of physiological regulation and suggests a function for islet serotonin. Given the much higher aggregate production and secretion of serotonin by the gut compared with that of the pancreatic islets, it seems unlikely that serotonin produced by the islet contributes substantially to systemic serotonin levels; but secretion by islet cells will primarily impact local concentrations and therefore could have autocrine or paracrine effects within the islet during the perinatal period and pregnancy analogous to the local effects of serotonin in the breast (47
). During pregnancy, the high levels of serotonin drive β-cell proliferation (46
). Since perinatal β-cells also rapidly proliferate (48
), serotonin may have similar functions in pregnant and perinatal β-cells.
We also found that β-cells and other islet cells express the serotonergic transcription factor Pet1/Fev. In the pancreas, expression of Fev
depends on the proendocrine transcription factor neurogenin3: neurogenin3 induced Fev
expression in vitro, pancreatic Fev
expression was lost in Neurog3−/−
embryos, and as we have previously described, Fev
expression is high in the transient neurogenin3-positive endocrine precursor cells during pancreatic development (32
). This neurogenin3 dependence, together with the in situ hybridization and lineage tracing data, demonstrates that Pet1 is expressed specifically in the islet lineage. In addition, as in the serotonergic neurons (10
expression in the pancreas requires the downstream target of neurogenin3, Nkx2.2, but not Nkx6.1 (itself regulated by Nkx2.2 [24
]). Our data from the Fev−/−
animals show, however, that none of these islet transcription factors depend on Pet1, thus placing Pet1 at the bottom of this cascade of transcription factors, as it is in the serotonergic neurons as well (10
In serotonergic neurons, Pet1 drives the expression of the final differentiation products that characterize the mature cells, such as serotonergic genes Tph2
). Surprisingly, in the pancreas Pet1 was not necessary for Tph2
expression, even though we found that it bound to Tph2
and other serotonergic genes. In contrast, Tph2
expression in the pancreas did depend on Nkx2.2 and Nkx6.1, as it does in serotonergic neurons (10
Instead, our data demonstrate that in the pancreas Pet1 regulates the expression of genes encoding key differentiated β-cell products, including the glucose transporter gene Slc2a2
, and both insulin genes. As a result, the Fev−/−
animals had defects in insulin production and secretion and impaired glucose clearance, despite compensatory increases in β-cell mass. Therefore, at the end of the transcription factor cascade, Pet1 guides the final differentiation and maturation of both serotonergic neurons and β-cells but does so by regulating overlapping but distinct sets of genes. It would be interesting to learn what role Pet1 may play in the expression of the β-cell glucose-sensing genes that are expressed in serotonergic neurons (14
The developmental and functional parallels between the serotonergic neurons in the brain and the β-cells in the pancreas may have important practical implications. It must be kept in mind that pharmacological or genetic manipulations targeting the serotonergic neurons may inadvertently impact the β-cells as well—and vice versa. For example, transgenic strategies using regulatory elements from the Fev or Pdx1 genes to target either cell type will likely target both cell types. Since both β-cells and serotonergic neurons regulate glucose metabolism, this genetic overlap may confound studies of energy homeostasis in mouse models using these genes for targeting. In addition, methods developed for generating these cells from stem cells or other sources must be assessed carefully, since the overlaps in gene expression profiles may lead to the misidentification of the generated cells.
Epidemiologists have long recognized an association between the risks of type 2 diabetes and depression (50
). Manifold causes likely contribute to this clinical association, but the genetic and functional similarities of the two key cell types involved in these diseases strongly suggest that some genetic or environmental insults may impair both serotonergic neurons and pancreatic β-cells and thus simultaneously increase the risk of both depression and type 2 diabetes. In addition, most drugs used to treat psychiatric disorders affect serotonergic signaling and may therefore also impact β-cells, especially during periods of high TPH activity in the islets, such as pregnancy and infancy.
Serotonin and insulin collaborate in an evolutionarily ancient partnership to regulate our response to changes in energy availability. Similarities in the function and development of the cells that produce serotonin and insulin reflect this evolutionary connection and have important implications for energy homeostasis and the pathology and treatment of diabetes.