Endothelin regulates neural crest deployment and fate to form great vessels through Dlx5/Dlx6-independent mechanisms.
Endothelin-1 (Edn1), originally identified as a vasoconstrictor peptide, is involved in the development of cranial/cardiac neural crest-derived tissues and organs. In craniofacial development, Edn1 binds to Endothelin type-A receptor (Ednra) to induce homeobox genes Dlx5/Dlx6 and determines the mandibular identity in the first pharyngeal arch. However, it remains unsolved whether this pathway is also critical for pharyngeal arch artery development to form thoracic arteries. Here, we show that the Edn1/Ednra signaling is involved in pharyngeal artery development by controlling the fate of neural crest cells through a Dlx5/Dlx6-independent mechanism. Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning, which include persistent first and second pharyngeal arteries, resulting in additional branches from common carotid arteries. Neural crest cell labeling with Wnt1-Cre transgene and immunostaining for smooth muscle cell markers revealed that neural crest cells abnormally differentiate into smooth muscle cells at the first and second pharyngeal arteries of Ednra knock-out embryos. By contrast, Dlx5/Dlx6 knockout little affect the development of pharyngeal arch arteries and coronary arteries, the latter of which is also contributed by neural crest cells through an Edn-dependent mechanism. These findings indicate that the Edn1/Ednra signaling regulates neural crest differentiation to ensure the proper patterning of pharyngeal arch arteries, which is independent of the regional identification of the pharyngeal arches along the dorsoventral axis mediated by Dlx5/Dlx6.
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ki-Sung
KS
Kim
Yuichiro
Y
Arima
Taro
T
Kitazawa
Koichi
K
Nishiyama
Rieko
R
Asai
Yasunobu
Y
Uchijima
Takahiro
T
Sato
Giovanni
G
Levi
Sachiko
S
Kitanaka
Takashi
T
Igarashi
Yukiko
Y
Kurihara
Hiroki
H
Kurihara
D000818:Animals; D001158:Arteries / Q000002:abnormalities / Q000378:metabolism*; D019521:Body Patterning / Q000235:genetics*; D001934:Branchial Region / Q000002:abnormalities / Q000378:metabolism*; D002454:Cell Differentiation; D004622:Embryo, Mammalian; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D059765:Homologous Recombination; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D009432:Neural Crest / Q000002:abnormalities / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; D019332:Endothelin-1; D018398:Homeodomain Proteins; D017466:Receptors, Endothelin; C045073:Cre recombinase; D019426:Integrases
Dlx code; Endothelin-1; Neural crest cell; Pharyngeal arch artery; Smooth muscle cell