Schwann cell-specific ablation of laminin gamma1 causes apoptosis and prevents proliferation.
To investigate the function of laminin in peripheral nerve development, we specifically disrupted the laminin gamma1 gene in Schwann cells. Disruption of laminin gamma1 gene expression resulted in depletion of all other laminin chains known to be expressed in Schwann cells. Schwann cells lacking laminin do not extend processes required for initiating axonal sorting and mediating axon-Schwann cell interaction. They fail to downregulate Oct-6 and arrest at the premyelinating stage. The impaired axon-Schwann cell interaction prevents phosphorylation of beta-neuregulin-1 receptors and results in decreased cell proliferation. Postnatally, laminin-null Schwann cells exhibit reduced phosphatidylinositol 3 (PI3)-kinase activity and activation of caspase cascades, leading to apoptosis. Injection of a laminin peptide into mutant sciatic nerves partially restores PI3-kinase activity and reduces apoptotic signals. These results demonstrate the following: (1) that laminin initiates axonal sorting and mediates axon-Schwann cell interactions required for Schwann cell proliferation and differentiation, and (2) that laminin provides a PI3-kinase/Akt-mediated Schwann cell survival signal.
Yu
Wei-Ming
WM
Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, New York 10021, USA.
Feltri
M Laura
ML
Wrabetz
Lawrence
L
Strickland
Sidney
S
Chen
Zu-Lin
ZL
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation; D003952:Diagnostic Imaging / Q000379:methods; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D007797:Laminin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D050816:Octamer Transcription Factor-6 / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism
D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D007211:Indoles; D007797:Laminin; D004676:Myelin Basic Protein; D016900:Neurofilament Proteins; D010455:Peptides; D012333:RNA, Messenger; C089141:laminin gamma 1; D050816:Octamer Transcription Factor-6; C007293:DAPI; D019869:Phosphatidylinositol 3-Kinases; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases; D001973:Bromodeoxyuridine