title: Apaf1 apoptotic function critically limits Sonic hedgehog signaling during craniofacial development.
abstract: Apaf1 is an evolutionarily conserved component of the apoptosome. In mammals, the apoptosome assembles when cytochrome c is released from mitochondria, binding Apaf1 in an ATP-dependent manner and activating caspase 9 to execute apoptosis. Here we identify and characterize a novel mouse mutant, yautja, and find it results from a leucine-to-proline substitution in the winged-helix domain of Apaf1. We show that this allele of Apaf1 is unique, as the yautja mutant Apaf1 protein is stable, yet does not possess apoptotic function in cell culture or in vivo assays. Mutant embryos die perinatally with defects in craniofacial and nervous system development, as well as reduced levels of apoptosis. We further investigated the defects in craniofacial development in the yautja mutation and found altered Sonic hedgehog (Shh) signaling between the prechordal plate and the frontonasal ectoderm, leading to increased mesenchymal proliferation in the face and delayed or absent ossification of the skull base. Taken together, our data highlight the time-sensitive link between Shh signaling and the regulation of apoptosis function in craniofacial development to sculpt the face. We propose that decreased apoptosis in the developing nervous system allows Shh-producing cells to persist and direct a lateral outgrowth of the upper jaw, resulting in the craniofacial defects we see. Finally, the novel yautja Apaf1 allele offers the first in vivo understanding of a stable Apaf1 protein that lacks a function, which should make a useful tool with which to explore the regulation of programmed cell death in mammals.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Long
authors.forename: W J
authors.initials: WJ
authors.lastname: Kaiser
authors.forename: E S
authors.initials: ES
authors.lastname: Mocarski
authors.forename: T
authors.initials: T
authors.lastname: Caspary
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D019465:Craniofacial Abnormalities / Q000196:embryology* / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D005838:Genotype; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D015398:Signal Transduction
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D053823:Hedgehog Proteins
references.citation: Nature. 2001 Dec 20-27;414(6866):909-12
references.pmid: 11780063
references.citation: Cell. 1997 Aug 8;90(3):405-13
references.pmid: 9267021
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7485-90
references.pmid: 9636176
references.citation: Nature. 1992 Apr 9;356(6369):494-9
references.pmid: 1560823
references.citation: Dev Biol. 2008 Oct 1;322(1):121-32
references.pmid: 18680740
references.citation: J Biol Chem. 2000 Oct 6;275(40):31199-203
references.pmid: 10940292
references.citation: Mol Cell. 2002 Feb;9(2):423-32
references.pmid: 11864614
references.citation: Dev Biol. 2000 Feb 15;218(2):248-58
references.pmid: 10656767
references.citation: Plast Reconstr Surg. 1996 Feb;97(2):313-20
references.pmid: 8559813
references.citation: Cell. 1997 May 16;89(4):629-39
references.pmid: 9160754
references.citation: Dev Biol. 2002 Jan 1;241(1):106-16
references.pmid: 11784098
references.citation: Development. 2003 May;130(9):1749-58
references.pmid: 12642481
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9683-7
references.pmid: 11504943
references.citation: Genetics. 2011 Jul;188(3):615-24
references.pmid: 21515572
references.citation: Histochem Cell Biol. 2006 Aug;126(2):149-58
references.pmid: 16816938
references.citation: Dev Biol. 2004 Dec 15;276(2):313-29
references.pmid: 15581867
references.citation: Genes Dev. 2001 Nov 15;15(22):2922-33
references.pmid: 11711427
references.citation: Cell Res. 2003 Dec;13(6):429-42
references.pmid: 14728799
references.citation: Cell. 1995 Oct 20;83(2):279-87
references.pmid: 7585945
references.citation: Dev Biol. 2000 Nov 15;227(2):648-60
references.pmid: 11071781
references.citation: Genes Dev. 1999 Dec 15;13(24):3179-84
references.pmid: 10617566
references.citation: Cell. 2010 Apr 30;141(3):446-57
references.pmid: 20434985
references.citation: Development. 2001 Oct;128(20):3975-86
references.pmid: 11641221
references.citation: Nature. 2005 Apr 14;434(7035):926-33
references.pmid: 15829969
references.citation: Cell. 1997 Nov 14;91(4):479-89
references.pmid: 9390557
references.citation: Exp Dermatol. 2004 Feb;13(2):93-7
references.pmid: 15009102
references.citation: Blood. 2006 Mar 1;107(5):1872-7
references.pmid: 16291596
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5913-9
references.pmid: 15755804
references.citation: Methods. 1999 Aug;18(4):473-80
references.pmid: 10491277
references.citation: Cell Death Differ. 2012 Jan;19(1):107-20
references.pmid: 21760595
references.citation: Development. 2009 Jan;136(1):107-16
references.pmid: 19036802
references.citation: Genesis. 2011 Apr;49(4):177-89
references.pmid: 21381182
references.citation: Hum Mol Genet. 2010 Apr 15;19(8):1577-92
references.pmid: 20106874
references.citation: J Biol Chem. 1998 Dec 11;273(50):33489-94
references.pmid: 9837928
references.citation: Genes Dev. 1996 May 1;10(9):1073-83
references.pmid: 8654923
references.citation: Teratology. 1997 Apr;55(4):231-40
references.pmid: 9216040
references.citation: Development. 2010 Oct;137(20):3405-9
references.pmid: 20826528
references.citation: Nature. 2011 Mar 17;471(7338):368-72
references.pmid: 21368762
references.citation: Dev Biol. 2009 Jan 1;325(1):200-10
references.pmid: 19013147
references.citation: Mech Dev. 1997 Nov;68(1-2):45-57
references.pmid: 9431803
references.citation: Mol Cell. 1998 Jun;1(7):949-57
references.pmid: 9651578
references.citation: Cell. 1998 Sep 18;94(6):739-50
references.pmid: 9753321
references.citation: Hum Mol Genet. 2000 Jun 12;9(10):1473-80
references.pmid: 10888597
references.citation: Dev Biol. 2007 Dec 1;312(1):103-14
references.pmid: 18028903
references.citation: Birth Defects Res A Clin Mol Teratol. 2010 Dec;88(12):1008-16
references.pmid: 20878909
references.citation: Cell. 1998 Sep 18;94(6):727-37
references.pmid: 9753320
references.citation: J Cell Sci. 2010 Oct 1;123(Pt 19):3209-14
references.pmid: 20844150
references.citation: Science. 2004 Sep 3;305(5689):1462-5
references.pmid: 15353802
references.citation: Dev Biol. 2005 Aug 1;284(1):48-61
references.pmid: 15979605
references.citation: Dev Cell. 2007 May;12(5):767-78
references.pmid: 17488627
references.citation: Development. 2007 Sep;134(18):3283-95
references.pmid: 17699607
references.citation: Development. 2002 Oct;129(19):4647-60
references.pmid: 12223420
references.citation: Cell. 1986 Mar 28;44(6):817-29
references.pmid: 3955651
references.citation: Dev Dyn. 2012 Feb;241(2):247-56
references.pmid: 22275045
references.citation: Development. 2001 Jul;128(14):2755-67
references.pmid: 11526081
references.citation: Histochemistry. 1993 Dec;100(6):431-40
references.pmid: 7512949