Laminins promote postsynaptic maturation by an autocrine mechanism at the neuromuscular junction.
A prominent feature of synaptic maturation at the neuromuscular junction (NMJ) is the topological transformation of the acetylcholine receptor (AChR)-rich postsynaptic membrane from an ovoid plaque into a complex array of branches. We show here that laminins play an autocrine role in promoting this transformation. Laminins containing the alpha4, alpha5, and beta2 subunits are synthesized by muscle fibers and concentrated in the small portion of the basal lamina that passes through the synaptic cleft at the NMJ. Topological maturation of AChR clusters was delayed in targeted mutant mice lacking laminin alpha5 and arrested in mutants lacking both alpha4 and alpha5. Analysis of chimeric laminins in vivo and of mutant myotubes cultured aneurally demonstrated that the laminins act directly on muscle cells to promote postsynaptic maturation. Immunohistochemical studies in vivo and in vitro along with analysis of targeted mutants provide evidence that laminin-dependent aggregation of dystroglycan in the postsynaptic membrane is a key step in synaptic maturation. Another synaptically concentrated laminin receptor, Bcam, is dispensable. Together with previous studies implicating laminins as organizers of presynaptic differentiation, these results show that laminins coordinate post- with presynaptic maturation.
Nishimune
Hiroshi
H
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. hnishimune@kumc.edu
Valdez
Gregorio
G
Jarad
George
G
Moulson
Casey L
CL
Müller
Ulrich
U
Miner
Jeffrey H
JH
Sanes
Joshua R
JR
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D002478:Cells, Cultured; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009469:Neuromuscular Junction / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
C501370:Lama4 protein, mouse; D007797:Laminin; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; C097043:laminin alpha5; C058783:laminin beta2; D049030:Dystroglycans; D000110:Acetylcholinesterase
Dev Biol. 2006 Aug 1;296(1):265-77
16750824
Am J Physiol Renal Physiol. 2008 Feb;294(2):F393-406
18032551
Cell. 2002 Sep 6;110(5):639-48
12230980
Nat Genet. 1997 Nov;17(3):318-23
9354797
Curr Opin Neurobiol. 2006 Feb;16(1):74-82
16386415
J Cell Biol. 1990 Oct;111(4):1685-99
2211832
Dev Cell. 2003 May;4(5):673-85
12737803
Hum Mol Genet. 1997 Jun;6(6):831-41
9175728
J Cell Biol. 1998 Dec 14;143(6):1713-23
9852162
Exp Neurol. 1983 May;80(2):361-82
6840244
J Biol Chem. 2001 Jul 6;276(27):24911-7
11342559
Cell. 1997 Aug 22;90(4):729-38
9288752
J Cell Sci. 2006 Jan 15;119(Pt 2):199-207
16410545
J Cell Biol. 1997 Dec 15;139(6):1507-21
9396756
Neuron. 2001 May;30(2):399-410
11395002
Hum Mol Genet. 2004 Dec 1;13(23):2947-57
15471888
J Cell Biol. 1997 Mar 10;136(5):1047-58
9060469
Neuron. 1997 Apr;18(4):623-35
9136771
J Biol Chem. 2000 Nov 10;275(45):35192-9
10934193
Behav Brain Res. 2001 Sep 28;124(1):33-46
11423164
J Cell Biol. 2002 May 27;157(5):883-95
12034776
Nature. 2004 Dec 2;432(7017):580-7
15577901
Dev Dyn. 2001 Sep;222(1):101-14
11507772
J Neurosci. 2006 Jan 18;26(3):934-47
16421313
Eur J Neurosci. 1999 Oct;11(10):3457-67
10564354
Microsc Res Tech. 2000 Nov 1;51(3):280-301
11054877
PLoS One. 2008 Apr 30;3(4):e2084
18446215
J Neurosci. 1998 Feb 15;18(4):1250-60
9454835
Cell. 1997 Aug 22;90(4):717-27
9288751
Nat Rev Neurosci. 2001 Nov;2(11):791-805
11715056
J Cell Biol. 1999 May 3;145(3):619-31
10225961
Matrix Biol. 2006 Apr;25(3):189-97
16413178
J Cell Biol. 1997 Oct 6;139(1):181-91
9314538
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11088-93
16043708
J Biol Chem. 2002 May 24;277(21):18928-37
11886875
Neuron. 1999 May;23(1):33-44
10402191
Nat Neurosci. 2001 Jun;4(6):597-604
11369940
J Neurosci. 2004 Sep 15;24(37):8181-91
15371519
Dev Biol. 1996 Feb 25;174(1):125-39
8626012
J Cell Biol. 2004 Mar 29;164(7):1077-87
15037598
J Biol Chem. 2002 Nov 22;277(47):44864-9
12244066
Dev Biol. 1987 Feb;119(2):390-401
3100362
J Electron Microsc (Tokyo). 1995 Apr;44(2):59-65
7650451
J Biol Chem. 1993 Jul 15;268(20):14972-80
8325873
Dev Biol. 2005 Jun 1;282(1):111-25
15936333
Nat Genet. 1999 Nov;23(3):338-42
10610181
J Cell Biol. 2003 Apr 14;161(1):187-96
12682087
J Cell Biol. 1997 May 5;137(3):685-701
9151674
Connect Tissue Res. 2005;46(3):142-52
16147852
Annu Rev Neurosci. 1999;22:389-442
10202544
Nature. 2001 Apr 26;410(6832):1057-64
11323662
Eur J Biochem. 2002 Jan;269(2):431-42
11856301
Microsc Res Tech. 2000 Nov 1;51(3):247-61
11054875
Neuron. 2000 Feb;25(2):279-93
10719885
J Biol Chem. 2007 May 18;282(20):14853-60
17383963
Neuron. 2005 May 19;46(4):569-79
15944126
Cell Tissue Res. 1999 Apr;296(1):183-90
10199978
Connect Tissue Res. 2005;46(4-5):193-9
16546822
Cell. 1994 Jun 3;77(5):663-74
8205616
Matrix Biol. 2000 Aug;19(4):309-17
10963991
Neuron. 1995 Jul;15(1):115-26
7619516
Development. 2005 Oct;132(20):4471-81
16162647
J Neurosci. 2000 May 15;20(10):3663-75
10804208
J Neurosci. 2006 Mar 15;26(11):2841-51
16540561
Dev Biol. 1982 Nov;94(1):11-22
7152099
Nature. 1995 Mar 16;374(6519):258-62
7885444
J Neurosci. 1983 May;3(5):1058-68
6341513
Cell. 1996 May 17;85(4):525-35
8653788
Nature. 1992 Feb 20;355(6362):696-702
1741056
Tissue Cell. 1976;8(4):673-92
1020021
J Physiol. 2003 Feb 1;546(Pt 3):789-800
12563004
Neuron. 1994 May;12(5):1173-80
8185951
Nature. 1992 Dec 10;360(6404):588-91
1461282
J Cell Biol. 1995 May;129(4):1093-101
7744958
Matrix Biol. 2005 Aug;24(5):326-32
15979864
Genesis. 2000 Feb;26(2):162-4
10686619
J Neurosci. 2008 Mar 26;28(13):3333-40
18367600
J Cell Biol. 2003 Mar 3;160(5):741-52
12604589
J Cell Biol. 2001 Feb 5;152(3):435-50
11157973
Nature. 1998 Jun 18;393(6686):698-701
9641682
Cell. 1994 Jun 3;77(5):675-86
8205617