Characteristic defects in neural crest cell-specific Galphaq/Galpha11- and Galpha12/Galpha13-deficient mice.
The endothelin/endothelin receptor system plays a critical role in the differentiation and terminal migration of particular neural crest cell subpopulations. Targeted deletion of the G-protein-coupled endothelin receptors ET(A) and ET(B) was shown to result in characteristic developmental defects of derivatives of cephalic and cardiac neural crest and of neural crest-derived melanocytes and enteric neurons, respectively. Since both endothelin receptors are coupled to G-proteins of the G(q)/G(11)- and G(12)/G(13)-families, we generated mouse lines lacking Galpha(q)/Galpha(11) or Galpha(12)/Galpha(13) in neural crest cells to study their roles in neural crest development. Mice lacking Galpha(q)/Galpha(11) in a neural crest cell-specific manner had craniofacial defects similar to those observed in mice lacking the ET(A) receptor or endothelin-1 (ET-1). However, in contrast to ET-1/ET(A) mutant animals, cardiac outflow tract morphology was intact. Surprisingly, neither Galpha(q)/Galpha(11)- nor Galpha(12)/Galpha(13)-deficient mice showed developmental defects seen in animals lacking either the ET(B) receptor or its ligand endothelin-3 (ET-3). Interestingly, Galpha(12)/Galpha(13) deficiency in neural crest cell-derived cardiac cells resulted in characteristic cardiac malformations. Our data show that G(q)/G(11)- but not G(12)/G(13)-mediated signaling processes mediate ET-1/ET(A)-dependent development of the cephalic neural crest. In contrast, ET-3/ET(B)-mediated development of neural crest-derived melanocytes and enteric neurons appears to involve G-proteins different from G(q)/G(11)/G(12)/G(13).
Dettlaff-Swiercz
Dagmara A
DA
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Wettschureck
Nina
N
Moers
Alexandra
A
Huber
Katrin
K
Offermanns
Stefan
S
D000818:Animals; D015153:Blotting, Western; D019465:Craniofacial Abnormalities / Q000235:genetics*; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000172:deficiency*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency*; D017353:Gene Deletion; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006652:Histological Techniques; D017403:In Situ Hybridization; D008544:Melanocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D017466:Receptors, Endothelin / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism
D017931:DNA Primers; D017466:Receptors, Endothelin; D001616:beta-Galactosidase; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11