The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis.
The c-Jun NH(2)-terminal kinase (JNK) group of mitogen-activated protein kinases is activated in response to a wide array of cellular stresses and proinflammatory cytokines. Roles for JNK in the developing nervous system and T-cell-mediated immunity have been established by detailed studies of mice with compound mutations in the Jnk genes. However, little is known concerning the roles of JNK in other mammalian tissues. Mice lacking both of the ubiquitously expressed isoforms (JNK1 and -2) die during midgestation with neural tube closure defects and brain abnormalities. Here we show that JNK-deficient mice exhibit delayed epithelial development in the epidermis, intestines, and lungs. In addition, JNK-deficient mice exhibit an eyelid closure defect associated with markedly reduced epidermal growth factor (EGF) receptor function, and loss of expression of the ligand EGF. We further demonstrate that adult mice lacking either JNK1 or -2 display striking differences in epidermal proliferation and differentiation, indicative of distinct roles for these kinases in the skin. We conclude that JNK is necessary for epithelial morphogenesis and is an essential regulator of signal transduction by the EGF receptor in the epidermis.
Weston
Claire R
CR
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Wong
Anthony
A
Hall
J Perry
JP
Goad
Mary E P
ME
Flavell
Richard A
RA
Davis
Roger J
RJ
D000818:Animals; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005143:Eyelids / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007422:Intestines / Q000002:abnormalities / Q000196:embryology / Q000648:ultrastructure; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000502:physiology*; D008168:Lung / Q000002:abnormalities / Q000196:embryology / Q000648:ultrastructure; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D015345:Oligonucleotide Probes / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000196:embryology* / Q000201:enzymology; D014059:Tongue / Q000002:abnormalities / Q000196:embryology / Q000648:ultrastructure
D007527:Isoenzymes; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases