Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth.
Reelin is an extracellular matrix protein with various functions during development and in the mature brain. It activates different signaling cascades in target cells, one of which is the phosphatidylinositol 3-kinase (PI3K) pathway, which we investigated further using pathway inhibitors and in vitro brain slice and neuronal cultures. We show that the mTor (mammalian target of rapamycin)-S6K1 (S6 kinase 1) pathway is activated by Reelin and that this depends on Dab1 (Disabled-1) phosphorylation and activation of PI3K and Akt (protein kinase B). PI3K and Akt are required for the effects of Reelin on the organization of the cortical plate, but their downstream partners mTor and glycogen synthase kinase 3beta (GSK3beta) are not. On the other hand, mTor, but not GSK3beta, mediates the effects of Reelin on the growth and branching of dendrites of hippocampal neurons. In addition, PI3K fosters radial migration of cortical neurons through the intermediate zone, an effect that is independent of Reelin and Akt.
Jossin
Yves
Y
Université Catholique de Louvain, Center for Neurosciences, Avenue E. Mounier, 73, DENE 7382, B1200 Brussels, Belgium.
Goffinet
André M
AM
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D003712:Dendrites / Q000502:physiology* / Q000648:ultrastructure; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D015816:Cell Adhesion Molecules, Neuronal; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D038362:Glycogen Synthase Kinase 3; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000091042:Reelin Protein; D019893:Ribosomal Protein S6 Kinases; D012697:Serine Endopeptidases; D058570:TOR Serine-Threonine Kinases; C103773:Dab1 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse
Nat Med. 2002 Oct;8(10):1145-52
12244301
Nat Med. 2002 Oct;8(10):1153-60
12244302
J Biol Chem. 2002 Dec 20;277(51):49958-64
12376533
Curr Biol. 2003 Jan 8;13(1):18-26
12526740
FASEB J. 2003 Feb;17(2):295-7
12490540
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5479-84
12707415
Nature. 2003 May 22;423(6938):435-9
12761548
Cereb Cortex. 2003 Jun;13(6):607-11
12764035
Brain Res Mol Brain Res. 2003 Jul 23;115(2):121-9
12877983
J Biol Chem. 2003 Oct 3;278(40):38772-9
12882964
Mol Cell Biol. 2003 Oct;23(20):7210-21
14517291
FEBS Lett. 2003 Oct 9;553(1-2):173-8
14550568
Brain Res Mol Brain Res. 2003 Oct 7;117(2):152-9
14559149
J Neurosci. 2003 Oct 29;23(30):9953-9
14586026
Mol Cell Biol. 2004 Nov;24(21):9508-16
15485918
Neurosci Lett. 1992 Dec 14;148(1-2):202-6
1284442
J Neurosci. 1997 Jan 1;17(1):23-31
8987733
Curr Biol. 1997 Apr 1;7(4):261-9
9094314
Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1432-7
9465032
Dev Cell. 2006 Dec;11(6):859-71
17141160
Cereb Cortex. 2007 Jan;17(1):211-20
16481563
Neurosci Biobehav Rev. 2006;30(8):1065-77
16769115
J Neurosci. 2007 Apr 18;27(16):4243-52
17442808
Dev Cell. 2007 Jun;12(6):957-71
17543867
Nat Cell Biol. 2004 Nov;6(11):1122-8
15467718
J Neurochem. 1999 Nov;73(5):2073-83
10537067
Neuron. 1999 Oct;24(2):481-9
10571241
Chem Biol. 2000 Oct;7(10):793-803
11033082
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3477-82
11248103
J Neurochem. 2001 Aug;78(3):468-81
11483649
J Cell Biol. 2001 Oct 1;155(1):65-76
11581286
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13796-801
11707573
J Med Chem. 2002 Mar 14;45(6):1292-9
11881998
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3221-6
9501244
Nat Genet. 1998 Aug;19(4):333-9
9697693
Nature. 1998 Sep 10;395(6698):194-8
9744280
Cell. 1999 Jun 11;97(6):689-701
10380922
Development. 2004 Dec;131(24):6023-31
15537685
Mol Neurobiol. 2004 Dec;30(3):225-51
15655250
Science. 2005 Feb 18;307(5712):1098-101
15718470
Development. 2005 Mar;132(6):1175-85
15703280
Mol Cell Biol. 2005 Apr;25(7):2593-606
15767666
Curr Opin Cell Biol. 2005 Apr;17(2):158-66
15780592
J Biol Chem. 2005 Jul 8;280(27):25485-90
15899889
J Biol Chem. 2005 Jul 15;280(28):26089-93
15905173
Cereb Cortex. 2005 Aug;15(8):1134-45
15590913
Neuron. 2005 Aug 18;47(4):567-79
16102539
J Neurosci. 2005 Sep 14;25(37):8578-86
16162939
Development. 2005 Nov;132(21):4709-18
16207762
J Biol Chem. 2005 Dec 9;280(49):40406-16
16221682
J Neurosci. 2005 Dec 7;25(49):11300-12
16339025
Nat Cell Biol. 2006 Jan;8(1):17-26
16341208
J Neurosci. 2006 Feb 8;26(6):1767-75
16467525
Int Rev Neurobiol. 2005;71:383-417
16512359
Mol Cell. 2006 Apr 21;22(2):159-68
16603397
Mol Biol Cell. 2006 May;17(5):2267-77
16525023
Genes Dev. 2006 Jun 1;20(11):1511-24
16705040
J Biol Chem. 2006 Jun 16;281(24):16591-8
16611631
Cell. 2006 Oct 6;127(1):125-37
16962653
Mol Cell Biol. 2006 Nov;26(21):8042-51
16923958
Cell. 2002 May 31;109(5):611-23
12062104
J Neurochem. 2002 Jun;81(5):1073-83
12065620
Mol Cell Biol. 2003 Nov;23(22):8058-69
14585966
Nat Genet. 2003 Nov;35(3):270-6
14578885
J Neurosci. 2003 Nov 5;23(31):9996-10001
14602813
J Biol Chem. 2003 Nov 14;278(46):45937-45
12928438
Cancer Res. 2003 Dec 1;63(23):8451-60
14679009
Cancer Cell. 2003 Dec;4(6):463-76
14706338
Neuron. 2004 Jan 8;41(1):71-84
14715136
J Neurosci. 2004 Jan 14;24(2):514-21
14724251
Curr Biol. 2004 Apr 6;14(7):606-10
15062102
Neuron. 2004 Apr 22;42(2):197-211
15091337
Biochem Biophys Res Commun. 2004 May 21;318(1):204-12
15110774
Cancer Res. 2004 Jul 1;64(13):4394-9
15231645
Curr Biol. 2004 Jul 27;14(14):1296-302
15268862
J Cell Sci. 2004 Sep 1;117(Pt 19):4527-36
15316068
Nat Cell Biol. 2002 Jul;4(7):513-8
12080345
J Biol Chem. 2002 Aug 9;277(32):28706-13
12042314