Microanatomy of axon/glial signaling during Wallerian degeneration.
How do myelinated axons signal to the nuclei of cells that enwrap them? The cell bodies of oligodendrocytes and Schwann cells are segregated from axons by multiple layers of bimolecular lipid leaflet and myelin proteins. Conventional signal transduction strategies would seem inadequate to the challenge without special adaptations. Wallerian degeneration provides a model to study axon-to-Schwann cell signaling in the context of nerve injury. We show a hitherto undetected rapid, but transient, activation of the receptor tyrosine kinase erbB2 in myelinating Schwann cells after sciatic nerve axotomy. Deconvolving microscopy using phosphorylation state-specific antibodies shows that erbB2 activation emanates from within the microvilli of Schwann cells, in direct contact with the axons they enwrap. To define the functional role of this transient activation, we used a small molecule antagonist of erbB2 activation (PKI166). The response of myelinating Schwann cells to axotomy is inhibited by PKI166 in vivo. Using neuron/Schwann cell cocultures prepared in compartmentalized cell culture chambers, we show that even transient activation of erbB2 is sufficient to initiate Schwann cell demyelination and that the initiating functions of erbB2 are localized to Schwann cells.
Guertin
Amy D
AD
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Zhang
Dan P
DP
Mak
Kimberley S
KS
Alberta
John A
JA
Kim
Haesun A
HA
D000704:Analysis of Variance; D000818:Animals; D019771:Axotomy / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005727:Ganglia, Spinal / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D020880:Neuregulins / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D012583:Schwann Cells / Q000473:pathology; D020426:Sciatic Neuropathy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015222:Sodium Channels / Q000378:metabolism; D013997:Time Factors; D014855:Wallerian Degeneration / Q000473:pathology* / Q000503:physiopathology
D001973:Bromodeoxyuridine; D006023:Glycoproteins; D020929:Mitogen-Activated Protein Kinase Kinases; D004676:Myelin Basic Protein; D020880:Neuregulins; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D015222:Sodium Channels; C410026:PKI 166; C483804:Erbb2 protein, rat