Teratogen-induced activation of ERK, JNK, and p38 MAP kinases in early postimplantation murine embryos.
BACKGROUND
Although many teratogens are known to activate apoptotic pathways culminating in abnormal development, little is known about how the embryo transduces a teratogenic exposure into specific responses. Signal reception and transduction are regulated by a number of signal transduction pathways, including the extracellular signal-regulated protein kinases (ERKs), c-Jun N-terminal kinases (JNKs) and the stress-activated protein kinase, p38.


METHODS
To analyze the effects of teratogens on MAP kinases, we used whole embryo culture, Western blot analyses, and antibodies recognizing inactive or active MAP kinases, or both.


RESULTS
We show that heat shock (HS) induces a rapid, strong, but transient activation of ERK, JNK, and p38 with maximal activation occurring within 30 min of the heat shock. By contrast, cyclophosphamide (CP) and staurosporine (ST) failed to activate ERK or JNK during the time period studied (7. 5 hr). ST and CP did induce a low but reproducible activation of p38 beginning at around 3 hr and 5 hr, respectively, after the initiation of exposure. Previous work has shown that heat shock induces elevated cell death in the embryo, primarily in the developing neuroepithelium, but not in the embryonic heart. Thus, we also compared the activation of these three MAP kinase pathways in heads, hearts, and trunks isolated from day 9 embryos exposed to 43 degrees C for 15 min. The results show that ERK, JNK, and p38 are activated in heads, hearts, and trunks.


CONCLUSIONS
Our results show that day 9 embryos do activate MAP kinase signaling pathways in response to teratogenic exposures; however, activation of a particular pathway does not appear to be required for teratogen-induced apoptosis.
Mirkes
P E
PE
Birth Defects Research Laboratory, Division of Genetics and Development, Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. pemst@u.washington.edu
Wilson
K L
KL
Cornel
L M
LM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D046508:Culture Techniques; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000633:toxicity; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D006358:Hot Temperature / Q000009:adverse effects; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000633:toxicity; D013723:Teratogens / Q000633:toxicity*; D014018:Tissue Distribution; D048051:p38 Mitogen-Activated Protein Kinases
D013723:Teratogens; D003520:Cyclophosphamide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019311:Staurosporine; C011272:perfosfamide