erbb3 and erbb2 are essential for schwann cell migration and myelination in zebrafish.
BACKGROUND
Myelin is critical for efficient axonal conduction in the vertebrate nervous system. Neuregulin (Nrg) ligands and their ErbB receptors are required for the development of Schwann cells, the glial cells that form myelin in the peripheral nervous system. Previous studies have not determined whether Nrg-ErbB signaling is essential in vivo for Schwann cell fate specification, proliferation, survival, migration, or the onset of myelination.


RESULTS
In genetic screens for mutants with disruptions in myelinated nerves, we identified mutations in erbb3 and erbb2, which together encode a heteromeric tyrosine kinase receptor for Neuregulin ligands. Phenotypic analysis shows that both genes are essential for development of Schwann cells. BrdU-incorporation studies and time-lapse analysis reveal that Schwann cell proliferation and migration, but not survival, are disrupted in erbb3 mutants. We show that Schwann cells can migrate in the absence of DNA replication. This uncoupling of proliferation and migration indicates that erbb gene function is required independently for these two processes. Pharmacological inhibition of ErbB signaling at different stages reveals a continuing requirement for ErbB function during migration and also provides evidence that ErbB signaling is required after migration for proliferation and the terminal differentiation of myelinating Schwann cells.


CONCLUSIONS
These results provide in vivo evidence that Neuregulin-ErbB signaling is essential for directed Schwann cell migration and demonstrate that this pathway is also required for the onset of myelination in postmigratory Schwann cells.
Lyons
David A
DA
Department of Developmental Biology, Stanford University, California 94305, USA.
Pogoda
Hans-Martin
HM
Voas
Matthew G
MG
Woods
Ian G
IG
Diamond
Brianne
B
Nix
Rebecca
R
Arana
Naomi
N
Jacobs
Jennifer
J
Talbot
William S
WS
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D001483:Base Sequence; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology*; D002874:Chromosome Mapping; D018076:DNA, Complementary / Q000235:genetics; D018815:Genes, erbB / Q000235:genetics*; D018734:Genes, erbB-2 / Q000235:genetics*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism* / Q000502:physiology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; D020890:Neuregulin-1; D016590:Aphidicolin; D001973:Bromodeoxyuridine