TY - JOUR
T1 - Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development
AU - Huang, Wei
AU - Wang, Guangliang
AU - Delaspre, Fabien
AU - Vitery, Maria del Carmen
AU - Beer, Rebecca L.
AU - Parsons, Michael J.
N1 - Funding Information:
We thank Dr. V. Prince (University of Chicago, IL) for Neckless (nls) mutant fish and Dr. Ken Poss (Duke University, NC) for plasmids. We are grateful to SueJeanne Koh and Dr. Steven D. Leach for critical reading of this manuscript. This work was supported by the Juvenile Diabetes Research Foundation ( 17-2012-408 ), the JHU-UMD Diabetes Research Center ( P30DK079637 ), and the NIH ( R01DK080730 , R01HD058530 ). F. D. was supported by an MSCRF Postdoctoral Fellowship ( 2013-MSCRFF-050 ). R. L. B. was supported by an NIH Ruth L. Kirschstein NRSA ( 1F32DK101289 ). This work is dedicated to the memory of Larysa H. Pevny.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs.
AB - As the developing zebrafish pancreas matures, hormone-producing endocrine cells differentiate from pancreatic Notch-responsive cells (PNCs) that reside within the ducts. These new endocrine cells form small clusters known as secondary (2°) islets. We use the formation of 2° islets in the pancreatic tail of the larval zebrafish as a model of β-cell neogenesis. Pharmacological inhibition of Notch signaling leads to precocious endocrine differentiation and the early appearance of 2° islets in the tail of the pancreas. Following a chemical screen, we discovered that blocking the retinoic acid (RA)-signaling pathway also leads to the induction of 2° islets. Conversely, the addition of exogenous RA blocks the differentiation caused by Notch inhibition. In this report we characterize the interaction of these two pathways. We first verified that signaling via both RA and Notch ligands act together to regulate pancreatic progenitor differentiation. We produced a transgenic RA reporter, which demonstrated that PNCs directly respond to RA signaling through the canonical transcriptional pathway. Next, using a genetic lineage tracing approach, we demonstrated these progenitors produce endocrine cells following inhibition of RA signaling. Lastly, inhibition of RA signaling using a cell-type specific inducible cre/lox system revealed that RA signaling acts cell-autonomously in PNCs to regulate their differentiation. Importantly, the action of RA inhibition on endocrine formation is evolutionarily conserved, as shown by the differentiation of human embryonic stem cells in a model of human pancreas development. Together, these results revealed a biphasic function for RA in pancreatogenesis. As previously shown by others, RA initially plays an essential role during embryogenesis as it patterns the endoderm and specifies the pancreatic field. We reveal here that later in development RA is involved in negatively regulating the further differentiation of pancreatic progenitors and expands upon the developmental mechanisms by which this occurs.
KW - Differentiation
KW - Pancreas
KW - Progenitors
KW - Retinoic acid
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UR - http://www.scopus.com/inward/citedby.url?scp=84910112895&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2014.07.021
DO - 10.1016/j.ydbio.2014.07.021
M3 - Article
C2 - 25127993
AN - SCOPUS:84910112895
SN - 0012-1606
VL - 394
SP - 83
EP - 93
JO - Developmental biology
JF - Developmental biology
IS - 1
ER -