Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Ear Ossicles Development



Science 22 March 2013: Vol. 339 no. 6126 pp. 1453-1456

Dual Origin of the Epithelium of the Mammalian Middle Ear

Hannah Thompson, Abigail S. Tucker

Department of Craniofacial Development and Stem Cell Biology, King’s College London, Guy’s Hospital, London, UK, SE1 9RT.


The air-filled cavity and ossicles of the mammalian middle ear   conduct sound to the cochlea. Using transgenic mice, we show that the mammalian middle ear develops through cavitation of a neural crest mass. These cells, which previously underwent an epithelial-to-mesenchymal transformation upon leaving the neural tube, undergo a mesenchymal-to-epithelial transformation to form a lining continuous with the endodermally derived auditory tube. The epithelium derived from endodermal cells, which surrounds the auditory tube and eardrum, develops cilia, whereas the neural crest–derived epithelium does not. Thus, the cilia critical to clearing pathogenic infections from the middle ear are distributed according to developmental derivations. A different process of cavitation appears evident in birds and reptiles, indicating that this dual epithelium may be unique to mammals.

The mammalian middle ear is an air-filled cavity housed within the auditory bulla with three ossicles suspended within it, connecting the eardrum to the inner ear. The epithelial lining of the middle ear in the ventral region is continuous with the auditory (Eustachian) tube, which connects the middle ear to the pharynx. In the mouse, the ossicles condense within the neural crest–derived first and second pharyngeal arches, adjacent to the developing inner ear and dorsal to the tip of the first pharyngeal pouch. In early postnatal mice, the future middle ear cavity is filled with neural crest cells surrounding the developing ossicles, which are positioned in the dorsal region of the future cavity (the attic), in addition to mesodermal cells that will mature to form the middle ear muscles. A process called cavitation then occurs in which the neural crest cells are replaced by an air-filled cavity. which surrounds the ossicles and muscles, allowing free movement in response to sound. The whole cavity is lined by an epithelium.

The three-ossicle mammalian middle ear is very different from that of other land tetrapods, which possess a single ossicle, the two additional ossicles having evolved by a transformation of the original jaw joint. We therefore wanted to assess whether a similar break in the endoderm and influx of mesenchyme into the cavity occurred in nonmammals. In the chick and gecko, no rupture of the endoderm during middle ear development was observed using histology, and mesenchyme did not enter the cavity, which remained air-filled. In contrast, in another mammal, the shrew, a similar filling of the middle ear cavity to that in the mouse was observed during development. Further lineage analysis is necessary to assess whether the middle ear in nonmammals has a dual origin; however, it is interesting to note that a neural crest origin of the middle ear epithelium has not been reported after quail-chick neural crest grafts within this region. In addition, unlike the heterogeneous mammalian middle ear epithelium, no regional differences were found in the avian middle ear epithelium, with a fairly simple epithelium being observed in all regions. It is therefore possible that nonmammals adopt the endodermal model, whereas the mesenchymal model is specific to mammals and may have evolved in connection with the incorporation of the jaw joint into the ear, which required cavitation of a previously solid area of mesenchyme.

We have shown that the highly versatile neural crest cells can undergo a mesenchyme-to-epithelium transformation, but they are unable to form the complex pseudostratified ciliated epithelium associated with the endodermally derived part of the middle ear. This implies that there may be constraints limiting the ability of the neural crest to form advanced epithelial cell types. As the neural crest–derived epithelium is simple and unciliated, its function to clear away mucus and debris efficiently would be limited, compared to the endodermally derived epithelium, which provides a logical explanation for why middle ear infections are more common and more severe in the neural crest–lined attic than in the ventral endoderm–lined region of the cavity. The origin of the middle ear epithelium therefore may have a direct consequence for health of the mammalian ear.

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Science 22 March 2013: Vol. 339 no. 6126 pp. 1396-1397

A Transition in the Middle Ear

Donna M. Fekete, Drew M. Noden

1Department of Biological Sciences and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

2Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.


As a mammalian embryo develops, tubular tissues expand rapidly, often displacing resident mesenchymal cells, forming progressively enlarged areas such as the thoracic and abdominal cavities. Mechanistic explanations for such growth usually focus on cell proliferation and shape changes, or layering within the expanding tissue. Researchers reveal that formation of the mammalian middle ear cavity is much more dynamic than thought, involving a programmed rupture of the epithelium and its replacement by a completely different cell type. In identifying two distinct origins of the cells that line the middle ear cavity, the authors overturn a long-held tenet of human embryology in suggesting that the process may be unique to mammals, perhaps in association with the evolution of the three middle ear sound-conducting bones.

Cells that contribute to the mammalian middle ear (schematic of mouse shown) include loose mesenchymal cells from the neural crest and mesoderm and endodermal cells lining the pharyngeal cavity. As the otic vesicle invaginates from the surface ectoderm, the first pharyngeal pouch pushes toward the body wall. The tympanic membrane develops as a merger of endoderm, neural crest, and ectoderm cells. Neural crest cells coalesce to form precursors of the middle ear ossicles, followed by a rupture of the endoderm along the upper surface of the pharyngeal pouch. Neural crest mesenchymal cells transform into epithelial cells that fuse with endoderm to repair the lining of the cavity. The middle ear then fills with air through the auditory tube, its connection with the pharynx.

The middle ear cavity forms in two phases. Bilateral outgrowths of the oral cavity (the first pharyngeal pouches) extend into the future middle ear region. The pouches become surrounded with mesenchyme composed primarily of neural crest cells, which migrate from the neural groove and arise by a process of epithelial-to-mesenchymal transformation. During a second expansion, the three small bones (ossicles) of the middle ear, and the muscles and blood vessels associated with them, fully incorporate into the middle ear cavity. Aeration of the cavity allows the ossicles to freely move. The embryological connection between the middle ear and oral cavities is retained in the adult as the auditory tube.

This classical view of the embryological origin of the mammalian middle ear was deduced from static histological images and lineage tracing studies, primarily in birds. However, a 1959 report that examined the mastoid sinuses of human fetuses and infants observed that the sinuses become lined with endothelial-like cells that differentiate in situ. Cells lining the auditory tube are columnar and ciliated, a feature common to many embryonic endodermal cells. By contrast, the middle ear epithelial cells are flat and lack cilia. It was argued that these epithelial cells likely share the same mesodermal origin as those lining the sinuses, and must therefore go through a mesenchymal-to-epithelial transition. A rupture of the auditory tube would allow epithelia to directly contact mesenchymal populations and facilitate their merger into a contiguous epithelial sheet. However, this model never gained widespread acceptance.

Current researchers resurrect the 1959 model using modern cell fate-mapping techniques in the mouse to illustrate just such a dual origin of the middle ear epithelium, and define an unexpected alternative embryological origin for the nonciliated epithelial cells. They show that the upper (dorsal) half of the middle ear cavity is lined with epithelial cells arising from mesenchymal cells of neural crest origin, whereas the lower half and the auditory tube is lined with ciliated endodermal cells. At the tissue level, the cavitation of the middle ear is accompanied by negligible cell death and takes place in two successive steps. The first pharyngeal pouch encroaches into the future middle ear region. Its roof then ruptures, and the exposed cavity fills with mesenchymal cells (see the figure). This temporary breach in the endoderm was also observed in the rat. The mesenchymal cells then retreat dorsally, reestablishing a cavity in the middle ear. During this process, which occurs postnatally in the mouse, mesenchymal neural crest cells transition into an epithelial phenotype and close the roof of the cavity, but fail to become ciliated. It is unclear whether mesenchymal cells first epithelialize by attaching directly to the ragged edge of the endodermal sheet, or instead epithelialize as small patches that must subsequently be stitched together. The latter process seems advantageous, given a need to also line and aerate the convoluted mastoid sinuses. By the time the process is completed, there is only modest intermingling between the bone fide oral endoderm and the crest-derived epithelia. The same sharpness of boundary is a characteristic of crest-mesoderm interfaces between cartilages and bones elsewhere in the head.

Middle ear cavitation in birds apparently does not require a breach in the endoderm, and lineage tracing of the neural crest populations in avian embryos failed to note any crest contribution to the middle ear ectoderm. It will be interesting to examine sites where ossicles directly abut other tissues. The stapes, which is homologous to the columella of birds and reptiles fuses with mesodermal chondroblasts that form its footplate, whereas the malleus contacts the endoderm-derived inner tympanic epithelium.

Mesenchymal-to-epithelial transitions occur frequently during embryogenesis, with examples found during somitogenesis and vasculogenesis. Yet, the cellular and molecular mechanisms are not fully characterized, particularly for the neural crest. This includes not only the process of middle ear cavitation, but also the mesenchymal-to-epithelial transitions that give rise to the posterior corneal epithelium. These revelations should prompt a reexamination of processes underlying the embryonic expansion of other structures, especially the body cavities, for potential contributions by mesenchymal lineages. The realization that epithelial and mesenchymal lineages are naturally transformable during development further raises possibilities of using mesenchymal stem cells to repair or replace a broader range of tissues.

Motile cilia in the middle ear clear mucus and pathogens out of the cavity and into the throat. When this system breaks down, an infection can arise. This vital role of cilia argues for a thorough description of their distribution and embryological origins in humans. And knowledge of neural crest contributions not only to the ossicles, but also to the middle ear lining, could offer new insights into the causes of congenital anomalies leading to conductive hearing loss.

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