Partial rescue of the Tbx1 mutant heart phenotype by Fgf8: genetic evidence of impaired tissue response to Fgf8.
Tbx1 is the candidate gene of DiGeorge syndrome and is required in humans and mice for the development of the cardiac outflow tract (OFT) and aortic arch arteries. Loss of function mutants present with reduced cell proliferation and premature differentiation of cardiac progenitor cells of the second heart field (SHF). Tbx1 regulates Fgf8 expression hence the hypothesis that the proliferation impairment may contribute to the heart phenotype of mutants. Here we show that forced Fgf8 expression modifies and partially rescues the OFT septation defects of Tbx1 mutants but only if there is some residual expression of Tbx1. This genetic experiment suggests that Tbx1, directly or indirectly, affects tissue response to Fgf8. Indeed, Tbx1(-/-) mouse embryonic fibroblasts were unable to respond to Fgf8 added to the culture media and showed defective response of Erk1/2 and Rsk1. Our data suggest a coordinated pathway modulating Fgf8 ligand expression and tissue response to it in the SHF.
Vitelli
Francesca
F
Institute of Biosciences and Technologies, Texas A&M University, Houston, TX, USA.
Lania
Gabriella
G
Huynh
Tuong
T
Baldini
Antonio
A
D000818:Animals; D015153:Blotting, Western; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
C496457:Fgf8 protein, mouse; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D051524:Fibroblast Growth Factor 8; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse
Ann Med. 2002;34(3):148-56
12173684
Dev Cell. 2006 Jan;10(1):81-92
16399080
Genesis. 2007 Jul;45(7):470-5
17610275
Cell. 2007 Mar 9;128(5):947-59
17350578
Nat Genet. 1998 Feb;18(2):136-41
9462741
Development. 2006 Jun;133(12):2419-33
16720879
Dev Biol. 2002 Jul 15;247(2):237-50
12086464
Dev Biol. 2009 Apr 1;328(1):109-17
19389367
Development. 2002 Oct;129(19):4605-11
12223416
Development. 2006 Sep;133(18):3587-95
16914493
Dev Biol. 2006 Jul 15;295(2):559-70
16696966
Development. 2008 Nov;135(21):3611-22
18832393
Circ Res. 2009 Oct 23;105(9):842-51
19745164
Dev Biol. 2004 Mar 1;267(1):190-202
14975726
PLoS One. 2009 Jun 25;4(6):e6049
19557177
Hum Mol Genet. 2008 Jan 1;17(1):150-7
17916582