Partial loss of Ascl2 function affects all three layers of the mature placenta and causes intrauterine growth restriction.
Several imprinted genes have been implicated in the regulation of placental function and embryonic growth. On distal mouse chromosome 7, two clusters of imprinted genes, each regulated by its own imprinting center (IC), are separated by a poorly characterized region of 280kb (the IC1-IC2 interval). We previously generated a mouse line in which this IC1-IC2 interval has been deleted (Del(7AI) allele) and found that maternal inheritance of this allele results in low birth weights in newborns. Here we report that Del(7AI) causes a partial loss of Ascl2, a maternally expressed gene in the IC2 cluster, which when knocked out leads to embryonic lethality at midgestation due to a lack of spongiotrophoblast formation. The hypomorphic Ascl2 allele causes embryonic growth restriction and an associated placental phenotype characterized by a reduction in placental weight, reduced spongiotrophoblast population, absence of glycogen cells, and an expanded trophoblast giant cell layer. We also uncovered severe defects in the labyrinth layer of maternal mutants including increased production of the trilaminar labyrinth trophoblast cell types and a disorganized labyrinthine vasculature. Our results have important implications for our understanding of the role played by the spongiotrophoblast layer during placentation and show that regulation of the dosage of the imprinted gene Ascl2 can affect all three layers of the chorio-allantoic placenta.
Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
Rosemary
R
Oh-McGinnis
Aaron B
AB
Bogutz
Louis
L
Lefebvre
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002452:Cell Count; D002872:Chromosome Deletion; D007758:Ear, Inner / Q000002:abnormalities; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D010920:Placenta / Q000002:abnormalities*; D011247:Pregnancy; D014327:Trophoblasts / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D009687:Nuclear Proteins; C489311:Ascl2 protein, mouse; C109277:TSSC3 protein
Nature. 1994 Sep 22;371(6495):333-6
8090202
Mol Cell Biol. 2010 Jan;30(1):295-306
19884348
DNA Res. 2004 Oct 31;11(5):325-34
15747580
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12127-32
19564597
Placenta. 2006 Jun-Jul;27(6-7):540-9
16125225
Nat Genet. 2001 Mar;27(3):255-6
11242103
Mol Cell Biol. 2008 Feb;28(3):1104-13
18039842
Development. 2008 Jun;135(12):2083-91
18448564
Int J Dev Biol. 2002;46(4):459-66
12141432
Placenta. 2006 Aug;27(8):882-8
16269175
Genetics. 2010 Nov;186(3):917-27
20713691
Exp Cell Res. 2005 Jan 1;302(1):48-60
15541725
Dev Dyn. 2006 Dec;235(12):3280-94
17039549
Cell. 2009 Mar 6;136(5):903-12
19269367
Nucleic Acids Res. 2006 Jul 19;34(12):e88
16855283
Cell. 1993 Oct 8;75(1):73-82
8402902
Nature. 1995 Apr 13;374(6523):640-3
7715703
Hum Mol Genet. 2009 Nov 15;18(22):4255-67
19684026
Nat Genet. 2002 Nov;32(3):426-31
12410230
Mol Hum Reprod. 2000 Nov;6(11):1019-25
11044465
Dev Biol. 2002 Oct 15;250(2):358-73
12376109
Mol Reprod Dev. 1993 Oct;36(2):121-9
8257562
Nat Genet. 1998 Nov;20(3):309-11
9806555
Mol Cell. 2008 Oct 24;32(2):232-46
18951091
Mamm Genome. 1999 Dec;10(12):1150-9
10594239
Methods Mol Med. 2006;121:371-92
16251755
Nature. 2002 Jun 27;417(6892):945-8
12087403
Nature. 2000 May 25;405(6785):482-5
10839546
Placenta. 2002 Jan;23(1):3-19
11869088
Genes Dev. 1998 Oct 15;12(20):3162-7
9784491
EMBO J. 2008 Jan 9;27(1):168-78
18079696
BMC Dev Biol. 2010 May 11;10:50
20459838
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12412-7
8901595
Nat Genet. 2004 Dec;36(12):1291-5
15516931
Dev Dyn. 1998 Sep;213(1):27-38
9733098
J Mol Med (Berl). 2007 Apr;85(4):379-87
17180344
BMC Dev Biol. 2007 May 21;7:53
17517131
Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):162-7
9874789
Genes Dev. 1988 Dec;2(12A):1639-46
3215514
Nature. 2000 May 25;405(6785):486-9
10839547
Nat Genet. 2000 Jul;25(3):311-4
10888880
Mech Dev. 1998 May;73(2):183-91
9622625
Mech Dev. 1999 Sep;87(1-2):129-42
10495277
Nat Genet. 2004 Dec;36(12):1296-300
15516932
Genes Dev. 2006 May 15;20(10):1268-82
16702402
Mol Cell Biol. 2008 Feb;28(3):1092-103
18039841
Mech Dev. 2004 Oct;121(10):1199-210
15327781
BMC Genomics. 2008 Jul 28;9:352
18662396
Dev Biol. 2009 Dec 1;336(1):42-52
19778534
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7490-5
12032310
Nat Genet. 1995 Mar;9(3):235-42
7773285
J Assist Reprod Genet. 2002 May;19(5):240-4
12099555