Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm.
Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is an important goal, as such knowledge can help to identify new genes involved in cardiovascular disease. The transcription factor Tbx1 plays a vital role in PAA development and is a major contributor to cardiovascular disease associated with DiGeorge syndrome. In this report, we used various genetic approaches to reveal part of a signalling network by which Tbx1 controls PAA development in mice. We investigated the crucial role played by the homeobox-containing transcription factor Gbx2 downstream of Tbx1. We found that PAA formation requires the pharyngeal surface ectoderm as a key signalling centre from which Gbx2, in response to Tbx1, triggers essential directional cues to the adjacent cardiac neural crest cells (cNCCs) en route to the caudal PAAs. Abrogation of this signal generates cNCC patterning defects leading to PAA abnormalities. Finally, we showed that the Slit/Robo signalling pathway is activated during cNCC migration and that components of this pathway are affected in Gbx2 and Tbx1 mutant embryos at the time of PAA development. We propose that the spatiotemporal control of this tightly orchestrated network of genes participates in crucial aspects of PAA development.
Calmont
Amélie
A
Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Ivins
Sarah
S
Van Bueren
Kelly Lammerts
KL
Papangeli
Irinna
I
Kyriakopoulou
Vanessa
V
Andrews
William D
WD
Martin
James F
JF
Moon
Anne M
AM
Illingworth
Elizabeth A
EA
Basson
M Albert
MA
Scambler
Peter J
PJ
D000818:Animals; D001158:Arteries / Q000002:abnormalities / Q000033:anatomy & histology / Q000196:embryology*; D019521:Body Patterning / Q000502:physiology*; D001934:Branchial Region / Q000002:abnormalities / Q000098:blood supply / Q000196:embryology; D002465:Cell Movement / Q000502:physiology*; D004475:Ectoderm / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism; D006321:Heart / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology*; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins
D006023:Glycoproteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D020825:T-Box Domain Proteins; D000097905:Roundabout Proteins; C513182:Gbx2 protein, mouse; C491573:Tbx1 protein, mouse; C120566:slit protein, vertebrate
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