Induction of neuregulin signaling in mouse schwann cells in vivo mimics responses to denervation.
Neuregulins play crucial roles in early development of Schwann cells (SCs), but their roles in the activities of SCs during denervation and reinnervation of muscle are less clear. In the present study, the Tet-On system has been used in transgenic mice to enable inducible expression of a mutant, constitutively active neuregulin receptor (ErbB2) in SCs. This induction simulates neuregulin signaling to these cells. Reporter transgenes were used to show a tightly regulated, SC-selective expression in muscle. Induction leads to a number of changes in SCs at neuromuscular junctions that mimic the response to muscle denervation/reinnervation. These include process extension, soma migration, and proliferation. SCs also come to express nestin, a protein characteristic of their reaction to muscle denervation. This activation of SCs results in the sprouting of nerve terminals, and these sprouts follow the extensions of the SCs. However, these sprouts and their associated SCs disappear after the removal of the inducer. Last, induction of the active receptor is sufficient to rescue SCs in neonatal muscle from denervation-induced apoptosis. These findings show that the responses of SCs in muscle to denervation can be explained by induction of an autocrine/paracrine neuregulin signaling cascade suggested by previous molecular studies.
Hayworth
Christopher R
CR
Section of Neurobiology and Institute for Neuroscience, University of Texas, Austin, Texas 78712, USA.
Moody
Susan E
SE
Chodosh
Lewis A
LA
Krieg
Paul
P
Rimer
Mendell
M
Thompson
Wesley J
WJ
D000818:Animals; D001973:Bromodeoxyuridine; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular / Q000379:methods; D004318:Doxycycline / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009121:Muscle Denervation / Q000379:methods*; D009414:Nerve Growth Factors / Q000235:genetics; D020880:Neuregulins / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology* / Q000528:radiation effects; D013997:Time Factors
D001973:Bromodeoxyuridine; D004318:Doxycycline; D049452:Green Fluorescent Proteins; D009414:Nerve Growth Factors; D020880:Neuregulins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins