Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

Maryline Minoux; Claudius F Kratochwil; Sébastien Ducret; Shilu Amin; Taro Kitazawa; Hiroki Kurihara; Nicoletta Bobola; Nathalie Vilain; Filippo M Rijli

doi:10.1242/dev.098046

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

Maryline Minoux, Claudius F Kratochwil, Sébastien Ducret, Shilu Amin, Taro Kitazawa, Hiroki Kurihara, Nicoletta Bobola, Nathalie Vilain, Filippo M Rijli

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Tidsskrift	Development
Vol/bind	140
Nummer	21
Sider (fra-til)	4386-97
Antal sider	12
ISSN	0950-1991
DOI	https://doi.org/10.1242/dev.098046
Status	Udgivet - nov. 2013
Udgivet eksternt	Ja

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10.1242/dev.098046

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title = "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. ",

keywords = "Animals, Bone Morphogenetic Proteins/metabolism, Chromatin Immunoprecipitation, Congenital Abnormalities/genetics, Congenital Microtia, Ear/abnormalities, Ear Auricle/abnormalities, Ear Canal/abnormalities, Homeodomain Proteins/genetics, Immunohistochemistry, In Situ Hybridization, Intracellular Signaling Peptides and Proteins/metabolism, Mesoderm/cytology, Mice, Morphogenesis/genetics, Mutation/genetics, Neural Crest/cytology, Nuclear Proteins/metabolism, Protein Tyrosine Phosphatases/metabolism, Signal Transduction/physiology, Tamoxifen/administration & dosage",

author = "Maryline Minoux and Kratochwil, {Claudius F} and S{\'e}bastien Ducret and Shilu Amin and Taro Kitazawa and Hiroki Kurihara and Nicoletta Bobola and Nathalie Vilain and Rijli, {Filippo M}",

year = "2013",

month = nov,

doi = "10.1242/dev.098046",

language = "English",

volume = "140",

pages = "4386--97",

journal = "Development",

issn = "0950-1991",

publisher = "The Company of Biologists",

number = "21",

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TY - JOUR

T1 - Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

AU - Minoux, Maryline

AU - Kratochwil, Claudius F

AU - Ducret, Sébastien

AU - Amin, Shilu

AU - Kitazawa, Taro

AU - Kurihara, Hiroki

AU - Bobola, Nicoletta

AU - Vilain, Nathalie

AU - Rijli, Filippo M

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Morphogenetic Proteins/metabolism

KW - Chromatin Immunoprecipitation

KW - Congenital Abnormalities/genetics

KW - Congenital Microtia

KW - Ear/abnormalities

KW - Ear Auricle/abnormalities

KW - Ear Canal/abnormalities

KW - Homeodomain Proteins/genetics

KW - Immunohistochemistry

KW - In Situ Hybridization

KW - Intracellular Signaling Peptides and Proteins/metabolism

KW - Mesoderm/cytology

KW - Mice

KW - Morphogenesis/genetics

KW - Mutation/genetics

KW - Neural Crest/cytology

KW - Nuclear Proteins/metabolism

KW - Protein Tyrosine Phosphatases/metabolism

KW - Signal Transduction/physiology

KW - Tamoxifen/administration & dosage

U2 - 10.1242/dev.098046

DO - 10.1242/dev.098046

M3 - Journal article

C2 - 24067355

SN - 0950-1991

VL - 140

SP - 4386

EP - 4397

JO - Development

JF - Development

IS - 21

ER -

Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

Abstract

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