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J Biol Chem, Vol. 274, Issue 3, 1487-1494, January 15, 1999
,
From the The formation of parietal endoderm (PE) is one of
the first differentiation processes during mouse development and can be studied in vitro using F9 embryonal carcinoma (EC) cells.
Treatment of F9 EC cells with retinoic acid (RA) induces
differentiation toward primitive endoderm (PrE), while differentiation
toward PE is induced by subsequent addition of parathyroid hormone
(PTH) or PTH-related peptide (PTHrP). The signal transduction
mechanisms involved in this two-step process are largely unclear.
We show that the RA-induced differentiation toward PrE is accompanied
by a sustained increase in Ras activity and that ectopic expression of
oncogenic Ha-Ras is sufficient to induce PrE differentiation. Ras
activity subsequently decreases upon PTH-induced differentiation toward
PE. This is a necessary event, since expression of oncogenic Ha-Ras in
PrE-like cells prevents PTH-induced PE differentiation. Expression of
active PKA in PrE-like F9 cells mimics PTH-induced PE differentiation
and is again prevented by oncogenic Ha-Ras. The effect of oncogenic Ras
on both differentiation steps is abolished by the MEK inhibitor PD98059
and can be mimicked by constitutively active forms of Raf and MEK.
In conclusion, our data suggest that activation of the Ras/Erk is
sufficient to induce differentiation to PrE and to prevent subsequent
differentiation toward PE. Activation of PKA down-regulates Ras
activity, resulting in disappearance of this blockade and transmission
of signal(s) triggering PE differentiation.
Hubrecht Laboratory, Netherlands
Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht,
The Netherlands and the § Laboratory for Physiological
Chemistry, Utrecht University, Universiteitsweg 100, 3584 CG
Utrecht, The Netherlands
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