Barhl2 limits growth of the diencephalic primordium through Caspase3 inhibition of beta-catenin activation.
Little is known about the respective contributions of cell proliferation and cell death to the control of vertebrate forebrain growth. The homeodomain protein barhl2 is expressed in the diencephalons of Xenopus, zebrafish, and mouse embryos, and we previously showed that Barhl2 overexpression in Xenopus neuroepithelial cells induces Caspase3-dependent apoptosis. Here, barhl2 is shown to act as a brake on diencephalic proliferation through an unconventional function of Caspase3. Depletion of Barhl2 or Caspase3 causes an increase in diencephalic cell number, a disruption of the neuroepithelium architecture, and an increase in Wnt activity. Surprisingly, these changes are not caused by decreased apoptosis but instead, are because of an increase in the amount and activation of β-catenin, which stimulates excessive neuroepithelial cell proliferation and induces defects in β-catenin intracellular localization and an up-regulation of axin2 and cyclinD1, two downstream targets of β-catenin/T-cell factor/lymphoïd enhancer factor signaling. Using two different sets of complementation experiments, we showed that, in the developing diencephalon, Caspase3 acts downstream of Barhl2 in limiting neuroepithelial cell proliferation by inhibiting β-catenin activation. Our data argue that Bar homeodomain proteins share a conserved function as cell type-specific regulators of Caspase3 activities.
Institut de Biologie de l'Ecole Normale Supérieure, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8197, Institut National de la Santé et de la Recherche Médicale U1024, 75005 Paris, France.
Hugo A
HA
Juraver-Geslin
Jérome J
JJ
Ausseil
Marion
M
Wassef
Béatrice C
BC
Durand
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D060466:Axin Protein; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004027:Diencephalon / Q000166:cytology / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D060466:Axin Protein; C111729:Axin2 protein, mouse; C501324:Barhl2 protein, Xenopus; C485867:Barhl2 protein, mouse; C530105:Ccnd1 protein, mouse; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; D019938:Cyclin D1; C505409:Casp3 protein, mouse; D053148:Caspase 3
J Neurosci. 2001 Jul 1;21(13):4752-60
11425902
Gene Expr Patterns. 2006 Apr;6(4):347-52
16448861
Genes Dev. 2007 Dec 1;21(23):3181-94
18056428
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8498-502
7667318
Development. 2004 Apr;131(7):1607-18
14998930
J Neurosci. 2009 Apr 1;29(13):3992-4003
19339595
Curr Opin Genet Dev. 2006 Feb;16(1):51-9
16377174
Dev Cell. 2009 Jan;16(1):21-34
19154716
Nat Immunol. 2003 Oct;4(10):1016-22
12970760
Science. 2002 Jul 19;297(5580):365-9
12130776
Mol Cell Biol. 2008 Mar;28(6):1905-14
18212062
Dev Biol. 2000 Jun 1;222(1):124-34
10885751
Development. 2002 Oct;129(20):4807-19
12361972
J Neurosci. 2004 Mar 24;24(12):3104-14
15044550
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7
10318916
PLoS Genet. 2007 May 25;3(5):e78
17530925
Development. 2005 Apr;132(8):1807-18
15772136
Genes Dev. 2008 Sep 1;22(17):2308-41
18765787
Cell. 1999 Jan 22;96(2):235-44
9988218
Development. 2005 May;132(9):2147-55
15788459
Dev Biol. 2007 Feb 15;302(2):367-75
17098224
Nat Neurosci. 2004 Nov;7(11):1242-9
15494730
Nat Rev Neurosci. 2005 Jul;6(7):553-64
15959467
Genes Dev. 2007 Dec 1;21(23):3195-207
18056429
Nature. 1996 Nov 28;384(6607):368-72
8934524
Dev Biol. 2007 Apr 1;304(1):22-33
17222817
Trends Neurosci. 2000 Jul;23(7):291-7
10856938
EMBO J. 2005 Nov 2;24(21):3793-806
16222340
Development. 2004 May;131(10):2305-15
15102701
Science. 1997 Mar 21;275(5307):1784-7
9065401
Mol Cell Biol. 2002 Feb;22(4):1172-83
11809808
Dev Biol. 2003 Aug 1;260(1):31-45
12885553
Brain Res Brain Res Rev. 2003 Oct;43(2):179-91
14572913