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The Journal of Neuroscience, January 1, 2002, 22(1):239-247
Growth-Associated Protein-43 Is Required for Commissural Axon
Guidance in the Developing Vertebrate Nervous System
Yiping
Shen1, 2,
Shyamala
Mani2,
Stacy L.
Donovan2,
James E.
Schwob1, and
Karina F.
Meiri1
1 Department of Anatomy and Cellular Biology, Tufts
University School of Medicine, Boston, Massachusetts 02111, and
2 Programs in Cell and Molecular Biology and Neuroscience,
State University of New York Upstate Medical University, Syracuse, New
York 13210
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.
Key words:
anterior commissure; hippocampal commissure; corpus
callosum; GAP-43; F-actin; PKC; Slit-2
Copyright © 2002 Society for Neuroscience 0270-6474/02/221239-09$05.00/0
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