JNK initiates a cytokine cascade that causes Pax2 expression and closure of the optic fissure.
The c-Jun NH(2)-terminal kinase (JNK) group of mitogen-activated protein kinases is stimulated in response to a wide array of cellular stresses and proinflammatory cytokines. Mice lacking individual members of the Jnk family (Jnk1, Jnk2, and Jnk3) are viable and survive without overt structural abnormalities. Here we show that mice with a compound deficiency in Jnk expression can survive to birth, but fail to close the optic fissure (retinal coloboma). We demonstrate that JNK initiates a cytokine cascade of bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh) that induces the expression of the paired-like homeobox transcription factor Pax2 and closure of the optic fissure. Interestingly, the role of JNK to regulate BMP4 expression during optic fissure closure is conserved in Drosophila during dorsal closure, a related morphogenetic process that requires JNK-regulated expression of the BMP4 ortholog Decapentaplegic (Dpp).
Weston
Claire R
CR
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Wong
Anthony
A
Hall
J Perry
JP
Goad
Mary E P
ME
Flavell
Richard A
RA
Davis
Roger J
RJ
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D003103:Coloboma / Q000196:embryology* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004330:Drosophila / Q000196:embryology / Q000378:metabolism; D053823:Hedgehog Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism; D051379:Mice / Q000196:embryology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051762:PAX2 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases