Mouse Hoxa2 mutations provide a model for microtia and auricle duplication.
External ear abnormalities are frequent in newborns ranging from microtia to partial auricle duplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtia associated with an abnormal shape of the auricle. In mice, Hoxa2 inactivation at early gestational stages results in external auditory canal (EAC) duplication and absence of the auricle, whereas its late inactivation results in a hypomorphic auricle, mimicking the human HOXA2 mutant condition. By genetic fate mapping we found that the mouse auricle (or pinna) derives from the Hoxa2-expressing neural crest-derived mesenchyme of the second pharyngeal arch, and not from a composite of first and second arch mesenchyme as previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2-negative first arch mesenchyme and does not develop at the first pharyngeal cleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crest is sufficient to induce a complete duplication of the pinna and a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchyme lining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesis of the pinna through the BMP signalling pathway and expression of Eya1, which in humans is involved in branchio-oto-renal syndrome. Thus, Hoxa2 loss- and gain-of-function approaches in mice provide a suitable model to investigate the molecular aetiology of microtia and auricle duplication.
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Maryline
M
Minoux
Claudius F
CF
Kratochwil
Sébastien
S
Ducret
Shilu
S
Amin
Taro
T
Kitazawa
Hiroki
H
Kurihara
Nicoletta
N
Bobola
Nathalie
N
Vilain
Filippo M
FM
Rijli
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D000013:Congenital Abnormalities / Q000235:genetics*; D065817:Congenital Microtia; D004423:Ear / Q000002:abnormalities*; D054644:Ear Auricle / Q000002:abnormalities* / Q000196:embryology; D004424:Ear Canal / Q000002:abnormalities* / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009432:Neural Crest / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000008:administration & dosage
D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; C489833:Hoxa2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D013629:Tamoxifen; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases
Auricle; BMP; Craniofacial development; External auditory canal; External ear; Hox; Neural crest; Pharyngeal arch; Pinna