Fig. 4.

Blocking transactivation of the epidermal growth factor receptor (EGFR) by endogenous PGE₂ reduces intestinal crypt epithelial proliferation. Tyrphostin AG-1478 is a selective tyrosine kinase inhibitor that blocks phosphorylation of the EGFR. WT mice treated with tyrphostin from age 7 days to age 14 days had reduced frequency of crypt fission (A), fewer Lgr5⁺ crypt epithelial cells (B), and reduced Lgr5⁺ crypt epithelial stem cell proliferation (C) compared with wild-type (WT) control mice. Exogenous 16,16-dimethyl PGE₂ (dmPGE₂) failed to rescue these measures of crypt epithelial proliferation in tyrphostin-treated mice. D: positional distribution of 5-bromo-2-deoxyuridine (BrdU)-labeled intestinal crypt epithelial cells in 14-day-old WT mice. The highest rate of epithelial cell proliferation in control mice was in the range of position 4 to position 8. Tyrphostin treatment resulted in significantly decreased proliferation in positions 1 to 8 compared with controls. dmPGE₂ treatment of mice given tyrphostin failed to rescue BrdU⁺ epithelial cell proliferation in positions 1 to 6 but restored proliferation to control levels higher up in the crypt. Values are means ± SE for 8–15 mice/treatment group. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with WT control mice.