Craniofacial anomalies of the cultured mouse embryo induced by inhibition of sonic hedgehog signaling: an animal model of holoprosencephaly.
The pathogenesis of holoprosencephaly is multifactorial, and blockage of Sonic hedgehog signaling is one of the most important causative factors in animal models and human cases. In this study, the authors analyzed facial anomalies of mouse embryos, which were cultured in vitro and exposed to cyclopamine, an alkaloid blocker of Sonic hedgehog signaling. When cultured with cyclopamine for embryonic day 8.5 to 10.5, the whole body size was smaller than normal, and the distance and angle between the nasal placodes were remarkably reduced. Extension of the cranial surface vessels also was noted. No cyclopia was observed. Migration of the cranial neural crest cells seemed to be intact. Expressions of Patched-1 and Gli-1, downstream genes of Sonic hedgehog signaling, also were down-regulated in in situ hybridization and real-time reverse transcriptase-polymerase chain reaction analyses. The authors consider that these facial anomalies represent milder phenotypes of holoprosencephaly.
Nagase
Takashi
T
Department of Plastic and Reconstructive Surgery, University Hospital, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. nagaset-pla@h.u-tokyo.ac.jp
Nagase
Miki
M
Osumi
Noriko
N
Fukuda
Satoru
S
Nakamura
Shun
S
Ohsaki
Kanae
K
Harii
Kiyonori
K
Asato
Hirotaka
H
Yoshimura
Kotaro
K
D000818:Animals; D049628:Body Size / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D046149:Embryo Culture Techniques; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000139:chemically induced* / Q000235:genetics; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D009666:Nose / Q000002:abnormalities / Q000187:drug effects; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013723:Teratogens; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D014704:Veratrum Alkaloids / Q000009:adverse effects; D000071676:Zinc Finger Protein GLI1
D005136:Eye Proteins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; C000606236:PTCH1 protein, human; D051761:Paired Box Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000605732:Pax6 protein, mouse; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C465570:Shh protein, mouse; D013723:Teratogens; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine