PT  - JOURNAL ARTICLE
AU  - Yiping Shen
AU  - Shyamala Mani
AU  - Stacy L. Donovan
AU  - James E. Schwob
AU  - Karina F. Meiri
TI  - Growth-Associated Protein-43 Is Required for Commissural Axon Guidance in the Developing Vertebrate Nervous System
AID  - 10.1523/JNEUROSCI.22-01-00239.2002
DP  - 2002 Jan 01
TA  - The Journal of Neuroscience
PG  - 239--247
VI  - 22
IP  - 1
4099  - http://www.jneurosci.org/content/22/1/239.short
4100  - http://www.jneurosci.org/content/22/1/239.full
SO  - J. Neurosci.2002 Jan 01; 22
AB  - Growth-associated protein-43 (GAP-43) is a major growth cone protein whose phosphorylation by PKC in response to extracellular guidance cues can regulate F-actin behavior. Here we show that 100% of homozygote GAP-43 (−/−) mice failed to form the anterior commissure (AC), hippocampal commissure (HC), and corpus callosum (CC) in vivo. Instead, although midline fusion was normal, selective fasciculation between commissural axons was inhibited, and TAG-1-labeled axons tangled bilaterally into Probst's bundles. Moreover, their growth cones had significantly smaller lamellas and reduced levels of F-actin in vitro. Likewise, 100% of GAP-43 (+/−) mice with one disrupted allele also showed defects in HC and CC, whereas the AC was unaffected. Individual GAP-43 (+/−) mice could be assigned to two groups based on the amount that PKC phosphorylation of GAP-43 was reduced in neocortical neurons. In mice with ∼1% phosphorylation, the HC and CC were absent, whereas in mice with ∼10% phosphorylation, the HC and CC were smaller. Both results suggest that PKC-mediated signaling in commissural axons may be defective. However, although Probst's bundles formed consistently at the location of the glial wedge, both GAP-43 (−/−) and GAP-43 (+/+) cortical axons were still repulsed by Slit-2 in vitro, precluding failure of this deflective signal from the glial wedge as the source of the phenotype. Nonetheless, the data show that a functional threshold of GAP-43 is required for commissure formation and suggests that failure to regulate F-actin in commissural growth cones may be related to inhibited PKC phosphorylation of GAP-43.