The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain.
Self-renewal and proliferation of neural stem cells and the decision to initiate neurogenesis are crucial events directing brain development. Here we show that the ubiquitin ligase Huwe1 operates upstream of the N-Myc-DLL3-Notch pathway to control neural stem cell activity and promote neurogenesis. Conditional inactivation of the Huwe1 gene in the mouse brain caused neonatal lethality associated with disorganization of the laminar patterning of the cortex. These defects stemmed from severe impairment of neurogenesis associated with uncontrolled expansion of the neural stem cell compartment. Loss- and gain-of-function experiments in the mouse cortex demonstrated that Huwe1 restrains proliferation and enables neuronal differentiation by suppressing the N-Myc-DLL3 cascade. Notably, human high-grade gliomas carry focal hemizygous deletions of the X-linked Huwe1 gene in association with amplification of the N-myc locus. Our results indicate that Huwe1 balances proliferation and neurogenesis in the developing brain and that this pathway is subverted in malignant brain tumors.
Zhao
Xudong
X
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
D' Arca
Domenico
D
Lim
Wei Keat
WK
Brahmachary
Manisha
M
Carro
Maria Stella
MS
Ludwig
Thomas
T
Cardo
Carlos Cordon
CC
Guillemot
Francois
F
Aldape
Ken
K
Califano
Andrea
A
Iavarone
Antonio
A
Lasorella
Anna
A
D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C511877:Dll3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases
Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):375-9
8278397
Cancer Cell. 2006 May;9(5):391-403
16697959
Brain Res Dev Brain Res. 2003 Oct 10;145(1):1-8
14519488
Pac Symp Biocomput. 2009;:504-15
19209726
Biochim Biophys Acta. 2007 Dec;1776(2):125-37
17868999
Neuron. 2005 Oct 6;48(1):45-62
16202708
Mol Cell Biol. 2005 Apr;25(7):2819-31
15767685
Development. 2008 May;135(9):1575-87
18356248
J Neurosci. 2005 Jan 5;25(1):247-51
15634788
Science. 2007 Feb 2;315(5812):642-5
17204608
Nature. 2008 Oct 23;455(7216):1061-8
18772890
Neuron. 2008 May 22;58(4):519-31
18498734
Genes Dev. 2002 Apr 1;16(7):846-58
11937492
J Neurosci. 1995 Sep;15(9):6058-68
7666189
J Cell Biol. 2005 Sep 12;170(6):983-92
16144902
Genes Dev. 2006 Jun 1;20(11):1511-24
16705040
Nat Neurosci. 2005 Jun;8(6):709-15
15917835
Cell. 2005 Jul 1;121(7):1071-83
15989956
Cereb Cortex. 2007 Mar;17(3):632-42
16627858
Nat Cell Biol. 2008 Jun;10(6):643-53
18488021
Nat Rev Mol Cell Biol. 2005 Oct;6(10):777-88
16314867
J Cell Biol. 2007 Jul 30;178(3):465-76
17664336
Nat Genet. 1993 Sep;5(1):56-61
8220424
J Neurosci. 1995 Sep;15(9):6046-57
7666188
Genes Dev. 2002 Oct 15;16(20):2699-712
12381668
Genes Dev. 2008 Oct 15;22(20):2755-66
18923074
J Neurosci. 1993 Feb;13(2):820-33
8426239
Science. 1999 Nov 12;286(5443):1321-6
10558980
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7331-6
12777630
Mol Biol Cell. 2007 Sep;18(9):3340-50
17567951
Cell. 2005 Jul 1;121(7):1085-95
15989957
Nat Genet. 2005 Apr;37(4):382-90
15778709
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
Nature. 2007 Sep 20;449(7160):351-5
17721509
Exp Cell Res. 1999 May 1;248(2):509-19
10222142
Mol Cell Biol. 2007 Jun;27(11):3982-94
17371842
Neuron. 2008 Jun 26;58(6):832-46
18579075
Cold Spring Harb Symp Quant Biol. 2008;73:411-20
19329578
J Neurosci. 2002 Feb 1;22(3):639-43
11826093
Blood. 2000 Mar 15;95(6):2104-10
10706881
Cell. 2005 Nov 4;123(3):409-21
16269333
Nat Rev Neurosci. 2007 Jun;8(6):438-50
17514197
Cancer Cell. 2008 Jul 8;14(1):10-21
18598940