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Fig. 9. Notch regulates sequential recruitment of endocrine and exocrine cell types
in developing mouse pancreas. Simplified model summarizes current results
within the context of known lineage relationships
(Chiang and Melton, 2003;
Gu et al., 2003;
Gu et al., 2002;
Kawaguchi et al., 2002), as
well as prior studies of Notch signaling in developing mouse pancreas
(Apelqvist et al., 1999;
Hald et al., 2003;
Jensen et al., 2000a;
Jensen et al., 2000b;
Murtaugh et al., 2003).
Diagonal red line distinguishes cell types characterized by active Notch
signaling, indicated by Hes1-positivity, from those with an inactive
Notch pathway. Notch pathway activation inhibits early recruitment of
Ngn3-positive endocrine precursors from a common endocrine/exocrine
precursor pool, and also inhibits generation of differentiated acinar cells
from dedicated exocrine precursors. Between E10.5 and E12.5,
Ngn3-positive endocrine precursors are recruited from a
Ptf1-P48/Hes1-positive common precursor pool. Recruitment of
dedicated endocrine precursors in inhibited by Notch, thereby reserving an
undifferentiated cell population responsible for ongoing epithelial growth as
well as subsequent exocrine differentiation. By E13.5, ongoing
Ptf1-P48 expression marks a dedicated exocrine precursor pool.
Ongoing Notch activity within this pool results in an inactive Ptf1
transcriptional complex, allowing terminal acinar cell differentiation to be
avoided until Ptf1-independent influences of Ptf1-P48 on epithelial
morphogenesis are fully realized. Notch silencing at E14.5 allows onset of
Ptf1 activity and acinar cell differentiation. The persistence of
Notch-regulated precursor cells in adult pancreas remains uncertain.
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