RT Journal Article
SR Electronic
T1 Stress-Activated Protein Kinase MKK7 Regulates Axon Elongation in the Developing Cerebral Cortex
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 16872
OP 16883
DO 10.1523/JNEUROSCI.1111-11.2011
VO 31
IS 46
A1 Tokiwa Yamasaki
A1 Hiroshi Kawasaki
A1 Satoko Arakawa
A1 Kimiko Shimizu
A1 Shigeomi Shimizu
A1 Orly Reiner
A1 Hideyuki Okano
A1 Sachiko Nishina
A1 Noriyuki Azuma
A1 Josef M. Penninger
A1 Toshiaki Katada
A1 Hiroshi Nishina
YR 2011
UL http://www.jneurosci.org/content/31/46/16872.abstract
AB The c-Jun NH2-terminal protein kinase (JNK), which belongs to the mitogen-activated protein kinase family, plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 7 and MKK4. To elucidate the physiological functions of MKK7, we used Nestin-Cre to generate a novel mouse model in which the mkk7 gene was specifically deleted in the nervous system (Mkk7flox/flox Nestin-Cre mice). These mice were indistinguishable from their control littermates in gross appearance during embryogenesis but died immediately after birth without breathing. Histological examination showed that the mutants had severe defects in brain development, including enlarged ventricles, reduced striatum, and minimal axon tracts. Electron microscopy revealed abnormal accumulations of filamentous structures and autophagic vacuoles in Mkk7flox/flox Nestin-Cre brain. Further analysis showed that MKK7 deletion decreased numbers of TAG-1-expressing axons and delayed neuronal migration in the cerebrum. Neuronal differentiation was not altered. In utero electroporation studies showed that contralateral projection of axons by layer 2/3 neurons was impaired in the absence of MKK7. Moreover, MKK7 regulated axon elongation in a cell-autonomous manner in vivo, a finding confirmed in vitro. Finally, phosphorylation levels of JNK substrates, including c-Jun, neurofilament heavy chain, microtubule-associated protein 1B, and doublecortin, were reduced in Mkk7flox/flox Nestin-Cre brain. Our findings demonstrate that the phenotype of Mkk7flox/flox Nestin-Cre mice differs substantially from that of Mkk4flox/flox Nestin-Cre mice, and establish that MKK7-mediated regulation of JNK is uniquely critical for both axon elongation and radial migration in the developing brain.