TGF-beta isoform signaling regulates secondary transition and
mesenchymal-induced endocrine development in the embryonic mouse pancreas.
Authors Tulachan SS, Tei E, Hembree M, Crisera C, Prasadan K, Koizumi M, Shah S, Guo P,
Bottinger E, Gittes GK
Submitted By Submitted Externally on 9/2/2015
Status Published
Journal Developmental biology
Year 2007
Date Published 5/15/2007
Volume : Pages 305 : 508 - 521
PubMed Reference 17418116
Abstract Transforming growth factor-beta (TGF-beta) superfamily signaling has been
implicated in many developmental processes, including pancreatic development.
Previous studies are conflicting with regard to an exact role for TGF-beta
signaling in various aspects of pancreatic organogenesis. Here we have
investigated the role of TGF-beta isoform signaling in embryonic pancreas
differentiation and lineage selection. The TGF-beta isoform receptors (RI, RII
and ALK1) were localized mainly to both the pancreatic epithelium and mesenchyme
at early stages of development, but then with increasing age localized to the
pancreatic islets and ducts. To determine the specific role of TGF-beta
isoforms, we functionally inactivated TGF-beta signaling at different points in
the signaling cascade. Disruption of TGF-beta signaling at the receptor level
using mice overexpressing the dominant-negative TGF-beta type II receptor showed
an increase in endocrine precursors and proliferating endocrine cells, with an
abnormal accumulation of endocrine cells around the developing ducts of mid-late
stage embryonic pancreas. This pattern suggested that TGF-beta isoform signaling
may suppress the origination of secondary transition endocrine cells from the
ducts. Secondly, TGF-beta isoform ligand inhibition with neutralizing antibody
in pancreatic organ culture also led to an increase in the number of
endocrine-positive cells. Thirdly, hybrid mix-and-match in vitro recombinations
of transgenic pancreatic mesenchyme and wild-type epithelium also led to
increased endocrine cell differentiation, but with different patterns depending
on the directionality of the epithelial-mesenchymal signaling. Together these
results suggest that TGF-beta signaling is important for restraining the growth
and differentiation of pancreatic epithelial cells, particularly away from the
endocrine lineage. Inhibition of TGF-beta signaling in the embryonic period may
thus allow pancreatic epithelial cells to progress towards the endocrine lineage
unchecked, particularly as part of the secondary transition of pancreatic
endocrine cell development. TGF-beta RII in the ducts and islets may normally
serve to downregulate the production of beta cells from embryonic ducts.


Investigators with authorship
NameInstitution
Erwin BottingerMount Sinai School of Medicine

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