Diagnosis Kaga K, Asato H (eds): Microtia and Atresia – Combined Approach by Plastic and Otologic Surgery. Adv Otorhinolaryngol. Basel, Karger, 2014, vol 75, pp 30–35 (DOI: 10.1159/000350598)

Development of the Auricle and External Auditory Canal Hidenori Ozeki Department of Otolaryngology, Head & Neck Surgery, Kobe Red Cross Hospital, Kobe, Japan

Each organ of vertebrate animals is derived from the three germ layers called the ectoderm, mesoderm and endoderm, which are established at an early stage of embryonic life. As the structures characteristic to the head, six pairs of arches called brachial arches develop on the ventral side, and five pairs of brachial grooves develop between each brachial arch (fig. 1a). At the same time, five pairs of dents called brachial pouches develop on the endodermal side, which later differentiate into the pharynx [1]. The first brachial arch (maxillary/mandibular arch) differentiates into the Meckel cartilage, which gives rise to the malleus and incus. The second brachial arch (hyoid arch) differentiates into the Reichert cartilage, which gives rise to the stapes, styloid process, and suprahyoid region. The third brachial arch differentiates into the infrahyoid region (fig. 1b). Neural crest cells play an important role in the development processes of each organ corresponding to the position of the brachial arches [2]. Neural crest cells develop in the border area of surface ectoderm and neural ectoderm (fig. 2a, b), and they migrate into the brachial arch region (fig. 2c). They receive inducing signals from the surrounding tissues in the brachial arches where they are settled, and are involved in the position-specific morphogenesis of the brachial arches (to be explained below). Neural crest cells are therefore defined as one of the stem cells having the differentiation potency corresponding to the environment of the brachial arches.

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Emergence of Neural Crest Cells and Morphogenesis of the Branchial Arches

a

Incus

Malleus

b

Maxillary process Meckel cartilage

Stapes Meckel cartilage

The first branchial goove

1 Mandibular arch

2

3 4

Hyoid arch Cardiac prominence

Styloid process

1

Hyoid bone Thyroid cartilage

2

3

4 6

Cricoid cartilage Tracheal cartilage

Fig. 1. The characteristic structures of the human head and neck region. a The early human ­embryo. Brachial arches develop on the ventral side in the pattern of segmental constructions. Numbers 1–4 and 6 represent each brachial arch. b The segmental structures in the adult human.

Development of the Auricle

Development of the auricle in the human fetus starts with condensation of the mandibular arch (caudal side of the first brachial arch) and the hyoid arch at the distal portion of the first brachial groove in the 4th week of gestation. Six ridges, known as hillocks of His, develop on the surface of the two brachial arches in the 6th week of gestation, and they are fused to form the auricle in the 11th week (fig. 3). Thus, the tragus and helix develop from the mandibular arch, whereas the anthelix and antitragus are derived from the hyoid arch. However, it is also argued that only the tragus is derived from the mandibular arch and the other components of the auricle are from the hyoid arch; this topic remains controversial [1]. The configured auricle shifts upward from the cervical region at the late embryonic stage and is almost complete by the 32nd week of gestation.

The dents of the first brachial groove deeper in the 4th week of gestation to turn into the primitive EAC, and the tip is connected to directly above the first brachial pouch (tubotympanic recess), which grows from the endoderm in the 10th week (fig. 4) [1].

Development of the Auricle and EAC Kaga K, Asato H (eds): Microtia and Atresia – Combined Approach by Plastic and Otologic Surgery. Adv Otorhinolaryngol. Basel, Karger, 2014, vol 75, pp 30–35 (DOI: 10.1159/000350598)

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Development of the External Auditory Canal

Surface ectoderm Dorsal

Neural ectoderm (Neural plate)

a

Ventral Neural crest

b

Neural crest cells

c

Neural tube

Larynx derived from endoderm

Branchial arch

Fig. 2. Emergence and migration of neural crest cells. Neural crest cells arise in both ends of the neural plate during the process of invagination of the plate (a→b). The cells start to migrate to the brachial arch region.

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Ozeki Kaga K, Asato H (eds): Microtia and Atresia – Combined Approach by Plastic and Otologic Surgery. Adv Otorhinolaryngol. Basel, Karger, 2014, vol 75, pp 30–35 (DOI: 10.1159/000350598)

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It was suggested by gene-knockout experiments in mice that the tympanic ring derived from the first branchial arch is required for induction of elongation of these two lumens [3], and its relationship with atresia of the EAC in humans is attracting attention. At the stage when the primitive EAC and the tubotympanic recess are connected, mesoderm components infiltrate between them to become fibrous tissues. The ­eardrum in adults is divided into three layers. The outer layer of the eardrum ­connected to the EAC is derived from the epidermal ectoderm, the tunica propria of the eardrum from the mesoderm component above, and the inner layer of the eardrum connected to the tympanic mucosa from the endoderm (tubotympanic recess) [1].

a

b

c Helix

3

Anthelix

3 4

3 2 1

2

4 5

4

6

1

6

6

1

Maxillary arch

Hyoid arch

Tragus

The first branchial goove

5

2

5

Antitragus

Mandibular arch

Fig. 3. Morphogenesis of the auricle. a The six hillocks of His develop on the mandibular and hyoid arches at approximately 6 weeks’ gestation. b At approximately 7 weeks, the hillocks are fusing to form two folds surrounding the first brachial groove, which will give rise to the primitive auditory canal. c The adult auricle with the derivatives of the six hillocks numbered.

Inner ear Primitive external auditory canal

Malleus

Tympanic cavity Tubotympanic recess

Larynx

Development of the Auricle and EAC Kaga K, Asato H (eds): Microtia and Atresia – Combined Approach by Plastic and Otologic Surgery. Adv Otorhinolaryngol. Basel, Karger, 2014, vol 75, pp 30–35 (DOI: 10.1159/000350598)

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Fig. 4. Morphogenesis of the mammalian external ear canal. The two lumens, the primitive external canal and the tubotympanic recess, are induced to connect with each other. The former is derived from the first brachial groove and the latter from the first brachial pouch. The ossicles, shown as ‘malleus’ in this figure, are buried in the mesoderm at this embryonic stage.

Maxillary arch Migration of ETAR positive neural crest cells ET-1-positive region

Activation of Gq/11

Expression of Dlx5/6

Specification of mandibular identity

Mandibular arch Dorsal

Hyoid arch

Ventral

Fig. 5. The role of ET-1/ETAR signaling in the brachial arch region. ET-1 is secreted in the ventral region of the mandibular and hyoid arches, where ETAR-positive neural crest cells receive the ET-1 signal. Then, the mandibular arch initiates the development to the mandible.

As explained above, neural crest cells are involved in formation of the branchial arch, and the molecular groups mediating this action were recently elucidated. One of them, endothelin-1 (ET-1), is secreted from vascular endothelial cells and isolated as a 21-amino acid peptide with vasoconstrictor activity [4]. Expression of the ET-1 gene, which codes this protein in the branchial arch region was later found and analysis of ET-1 gene-deficient mice demonstrated the contribution of ET-1 to ­morphogenesis of the brachial arch [4]. ET-1 is secreted in the branchial arch region, and neural crest cells that express endothelin-1 receptor type A (ETAR) migrate into that region. The regional intercellular interactions between ET-1 and ETAR activate G-protein Gq/11, leading to the expression of homeobox transcription factor Dlx5/6 at the distal portion of the mandibular and hyoid arches. The mandibular arch thus acquires its identity (fig. 5). This identity is lost with deficiency of the ET-1 gene, and the mandibular arch performs morphogenesis as the maxillary arch, which is the ‘default’ state of the first branchial arch. External ear anomalies due to dysplasia of the branchial arch, such as auricle hypoplasia and deficit of the EAC, were observed in ET-1 gene-deficient mice. Deformation of the auditory ossicles (incus-like deformation of the malleus, lack of the incu-

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Ozeki Kaga K, Asato H (eds): Microtia and Atresia – Combined Approach by Plastic and Otologic Surgery. Adv Otorhinolaryngol. Basel, Karger, 2014, vol 75, pp 30–35 (DOI: 10.1159/000350598)

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Endothelin-1 and Branchial Arch Morphogenesis

dostapedial joint) was also observed in the middle ear. The structures of the inner ear, which are derived not from the branchial arch but from the otocyst, were normal [6]. Abnormality of the branchial arch structures above is partially similar to mandibular hypoplasia and anomalies of the auditory organ in patients with microtia. It is hoped that further elucidation of the mechanism of onset of anomalies in the human auditory organ will come with future investigations.

References   4 Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T: A novel potent vasoconstrictor peptide producedby vascular endothelial cells. Nature 1988;332:411–415.   5 Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N: Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 1994;368:703–710.   6 Ozeki H, Kurihara Y, Tonami K, Watanabe S, Kurihara H: Endothelin-1 regulates the dorsoventral brachial arch patterning in mice. Mech Dev 2004; 121: 387–395.

Hidenori Ozeki Department of Otolaryngology, Head & Neck Surgery Kobe Red Cross Hospital 1-3-1 Wakihamakaigandori, Chuo-Ku, Kobe 651-0073 (Japan) E-Mail [email protected]

Development of the Auricle and EAC Kaga K, Asato H (eds): Microtia and Atresia – Combined Approach by Plastic and Otologic Surgery. Adv Otorhinolaryngol. Basel, Karger, 2014, vol 75, pp 30–35 (DOI: 10.1159/000350598)

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 1 Gulya AJ: Developmental anatomy of the ear; in Glasscock ME, Shambaugh GE, Johnson GD (eds): Glasscock-Shambaugh’s Surgery of the Ear, ed 4. Philadelphia, Saunders, 1990, pp 5–33.   2 Le Douarin NM, Kalcheim C: The Neural Crest, ed 2. Cambridge, Cambridge University Press, 1999.   3 Mallo M, Gridley T: Development of the mammalian ear: coordinate regulation of formation of the tympanic ring and the external acoustic meatus. Development 1996;122:173–179.

Development of the auricle and external auditory canal.

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