Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells.
During vertebrate development, the endodermal germ layer becomes regionalized along its anteroposterior axis to give rise to a variety of organs, including the pancreas. Genetic studies in zebrafish and mice have established that the signaling molecule retinoic acid (RA) plays a crucial role in endoderm patterning and promotes pancreas development. To identify how RA signals to pancreatic progenitors in the endoderm, we have developed a novel cell transplantation technique, using the ability of the SOX32 transcription factor to confer endodermal identity, to selectively target reagents to (or exclude them from) the endodermal germ layer of the zebrafish. We show that RA synthesized in the anterior paraxial mesoderm adjacent to the foregut is necessary for the development of insulin-expressing beta-cells. Conversely, RA receptor function is required in the foregut endoderm for insulin expression, but not in mesoderm or ectoderm. We further show that activation of RA signal transduction in endoderm alone is sufficient to induce insulin expression. Our results reveal that RA is an instructive signal from the mesoderm that directly induces precursors of the endocrine pancreas. These findings suggest that RA will have important applications in the quest to induce islets from stem cells for therapeutic uses.
Stafford
David
D
The Committee on Developmental Biology, The University of Chicago, 1027 East 57th Street, IL 60637, USA.
White
Richard J
RJ
Kinkel
Mary D
MD
Linville
Angela
A
Schilling
Thomas F
TF
Prince
Victoria E
VE
D000818:Animals; D002454:Cell Differentiation; D004707:Endoderm / Q000166:cytology* / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D012176:Retinoids / Q000378:metabolism*; D055747:SOX Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism
D006609:High Mobility Group Proteins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D055747:SOX Transcription Factors; D014157:Transcription Factors; D029961:Zebrafish Proteins; C438614:sox32 protein, zebrafish