Convergence of the insulin and serotonin programs in the pancreatic β-cell.
OBJECTIVE
Despite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences.


METHODS
We used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas.


RESULTS
We found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In β-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance.


CONCLUSIONS
These studies demonstrate that a common transcriptional cascade drives the differentiation of β-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes.
Diabetes Center, University of California, San Francisco, San Francisco, California, USA.
Yasuharu
Y
Ohta
Yasuhiro
Y
Kosaka
Nina
N
Kishimoto
Juehu
J
Wang
Stuart B
SB
Smith
Gerard
G
Honig
Hail
H
Kim
Rosa M
RM
Gasa
Nicole
N
Neubauer
Angela
A
Liou
Laurence H
LH
Tecott
Evan S
ES
Deneris
Michael S
MS
German
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059326:Serotonergic Neurons / Q000378:metabolism; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
C484684:Fev protein, mouse; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; C000715627:Nkx2-2 protein, mouse; C491328:Nkx6-1 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D012701:Serotonin; D014365:Tryptophan Hydroxylase