Neurabin-I is phosphorylated by Cdk5: implications for neuronal morphogenesis and cortical migration.
The correct morphology and migration of neurons, which is essential for the normal development of the nervous system, is enabled by the regulation of their cytoskeletal elements. We reveal that Neurabin-I, a neuronal-specific F-actin-binding protein, has an essential function in the developing forebrain. We show that gain and loss of Neurabin-I expression affect neuronal morphology, neurite outgrowth, and radial migration of differentiating cortical and hippocampal neurons, suggesting that tight regulation of Neurabin-I function is required for normal forebrain development. Importantly, loss of Neurabin-I prevents pyramidal neurons from migrating into the cerebral cortex, indicating its essential role during early stages of corticogenesis. We demonstrate that in neurons Rac1 activation is affected by the expression levels of Neurabin-I. Furthermore, the Cdk5 kinase, a key regulator of neuronal migration and morphology, directly phosphorylates Neurabin-I and controls its association with F-actin. Mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of Neurabin-I overexpression both in vitro and in vivo, suggesting that Neurabin-I function depends, at least in part, on its phosphorylation status. Together our findings provide new insight into the signaling pathways responsible for controlled changes of the F-actin cytoskeleton that are required for normal development of the forebrain.
Causeret
Frédéric
F
Department of Cellular and Molecular Neuroscience, Imperial College School of Medicine, Charing Cross Campus, London W6 8RP, United Kingdom.
Jacobs
Tom
T
Terao
Mami
M
Heath
Owen
O
Hoshino
Mikio
M
Nikolic
Margareta
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D002522:Chlorocebus aethiops / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099273:Neurabins
D000199:Actins; D051360:Cyclin-Dependent Kinase 5; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020830:rac1 GTP-Binding Protein; D000099273:Neurabins
Nat Rev Neurosci. 2000 Dec;1(3):173-80
11257905
EMBO J. 1992 Aug;11(8):2909-17
1639063
J Biol Chem. 2001 Dec 28;276(52):49043-52
11604394
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6047-52
11972060
Mol Cell Biol. 2002 Jul;22(13):4690-701
12052877
Dev Biol. 1996 Mar 15;174(2):233-47
8631496
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11173-8
8855328
Mol Cell Biol. 1996 Nov;16(11):6486-93
8887677
Neuron. 1997 Jan;18(1):29-42
9010203
J Cell Biol. 1997 Nov 17;139(4):951-61
9362513
Nature. 1998 Sep 10;395(6698):194-8
9744280
Biochemistry. 1999 Sep 28;38(39):12943-9
10504266
Science. 2005 Feb 11;307(5711):929-32
15705853
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3489-94
15728359
Mol Biol Cell. 2005 May;16(5):2349-62
15743906
Neuroscientist. 2005 Jun;11(3):187-91
15911868
Neuron. 2005 Jul 7;47(1):85-100
15996550
Nat Cell Biol. 2006 Jan;8(1):17-26
16341208
Neuron. 2006 Apr 6;50(1):13-8
16600851
Mol Biol Cell. 2006 May;17(5):2391-400
16525025
Neuroscience. 2006 Jul 7;140(3):897-911
16600521
Cereb Cortex. 2006 Jul;16 Suppl 1:i35-45
16766706
Cereb Cortex. 2006 Jul;16 Suppl 1:i64-8
16766709
Nature. 2006 Aug 17;442(7104):814-7
16862120
Neuron. 2006 Sep 21;51(6):674-6
16982410
Development. 2007 Jan;134(2):237-49
17151015
Nat Neurosci. 2007 Jan;10(1):67-76
17143272
Cell. 2003 Aug 22;114(4):469-82
12941275
Biochem J. 2000 Jan 15;345 Pt 2:185-94
10620493
J Cell Sci. 2000 Mar;113 ( Pt 6):975-83
10683146
Neuron. 2001 Jan;29(1):229-42
11182094
J Neurosci. 2002 Sep 1;22(17):7548-57
12196578
J Biol Chem. 2003 Jan 10;278(2):1186-94
12417592
J Biol Chem. 2003 May 23;278(21):18833-41
12531897
Nucleic Acids Res. 2003 Jul 1;31(13):3635-41
12824383
Curr Opin Neurobiol. 2003 Jun;13(3):384-90
12850224
EMBO J. 2003 Aug 15;22(16):4190-201
12912917
Nat Neurosci. 2003 Dec;6(12):1277-83
14625554
Neuron. 2004 Jan 22;41(2):215-27
14741103
J Neurosci. 2004 May 5;24(18):4421-31
15128856
J Neurochem. 2004 Jul;90(2):317-24
15228588
J Cell Sci. 2004 Sep 15;117(Pt 20):4739-48
15331630
Neuron. 2004 Oct 14;44(2):321-34
15473970
J Biol Chem. 1992 Jul 5;267(19):13383-90
1618840
Nat Rev Mol Cell Biol. 2001 Oct;2(10):749-59
11584302