Mouse Hoxa2 mutations provide a model for microtia and auricle duplication
Abstract
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.
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There was a lack of HOX gene expression, which would indicate more caudal PAs.
“Furthermore, we noted a lack of HOX gene expression, which would indicate more caudal PAs (Extended Data Fig. 5)26.”
From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [26]
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- Authors
- Minoux, M., Kratochwil, C. F., Ducret, S., Amin, S., Kitazawa, T., Kurihara, H., Bobola, N., Vilain, N., & Rijli, F. M.
- Affiliations
- Inserm (FR)
- University of Basel (CH)
- Friedrich Miescher Institute (CH)
- University of Manchester (GB)
- The University of Tokyo (JP)
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2013-11-01
- Volume
- 140
- Issue
- 21
- Pages
- 4386-4397
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W1981246069
- Cited by
- 97
- References
- 59
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 6 · 2023: 10 · 2022: 13 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 3 · 2017: 9 · 2016: 6 · 2015: 10 · 2014: 2
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/E017355/1, BB/H018123/2)
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Genetics › Congenital Ear and Nasal Anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Surgery › Reconstructive Facial Surgery Techniques
- Keywords
- Hoxa2, microtia, external auditory canal, neural crest-derived mesenchyme, branchial arches, BMP signaling, EYA1, branchio-oto-renal syndrome, conditional gene expression, mouse model
- MeSH terms
- Congenital Abnormalities, Animals, Ear, Ear Canal, Immunohistochemistry, Mesoderm, Morphogenesis, Mutation, Neural Crest, Nuclear Proteins, Tamoxifen, Signal Transduction, Protein Tyrosine Phosphatases, In Situ Hybridization, Homeodomain Proteins, Bone Morphogenetic Proteins, Chromatin Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Mice, Ear Auricle, Congenital Microtia
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