Mammalian Middle Ear Research Articles

Fossils document evolutionary changes of jaw joint to mammalian middle ear.

The dual jaw joint of Morganucodon1,2 consists of the dentary-squamosal joint laterally and the articular-quadrate one medially. The articular-quadrate joint and its associated post-dentary bones constitute the precursor of the mammalian middle ear. Fossils documenting the transition from such a precursor to the mammalian middle ear are poor, resulting in inconsistent interpretations of this hallmark apparatus in the earliest stage of mammaliaform evolution1-5. Here we report mandibular middle ears from two Jurassic mammaliaforms: a new morganucodontan-like species and a pseudotribosphenic shuotheriid species6. The morganucodontan-like species shows many previously unknown post-dentary bone morphologies1,2 and exhibits features that suggest a loss of load-bearing function in its articular-quadrate joint. The middle ear of the shuotheriid approaches the mammalian condition in that it has features that are suitable for an exclusively auditory function, although the post-dentary bones are still attached to the dentary. With size reduction of the jaw-joint bones, the quadrate shifts medially at different degrees in relation to the articular in the two mammaliaforms. These changes provide evidence of a gradual loss of load-bearing function in the articular-quadrate jaw joint-a prerequisite for the detachment of the post-dentary bones from the dentary7-12 and the eventual breakdown of the Meckel's cartilage13-15 during the evolution of mammaliaforms.

Docodontans from the Lower Cretaceous of Yakutia, Russia: New insights into diversity, morphology, and phylogeny of Docodonta

Docodonta are the most abundant and taxonomically diverse group of mammaliaforms in the high paleolatitude Lower Cretaceous Teete locality in Yakutia, Russia. Docodontans are represented by the tegotheriids Khorotherium yakutense and Ergetiis ichchi gen. et sp. nov., and possibly two more taxa known from fragmentary specimens (Docodonta indet.). Ergetiis ichchi gen. et sp. nov. shows a reduction and posterior shift of the angular process of the dentary which could indicate a reduction of the mandibular middle ear potentially in a way analogous to the transitional mammalian middle ear of Eutriconodonta. A revised phylogenetic analysis of Docodonta suggests a stemward position of Docodontidae and a sister group relationship for Simpsonodontidae and Tegotheriidae.

Outstanding Discoveries in Paleomammalogy in the Last One and a Half Decade

Since the last comprehensive review of the then state-of-the-art progress in paleomammalogy in 2010, there has been substantial further advances in understanding the middle ear development and phylogeny of Mesozoic mammals, evolution of early primates, and so on. The post-dentary bone morphologies of two Jurassic mammaliaforms, Dianoconodon youngi and Feredocodon chowi, demonstrate the detachment mechanism of post-dentary bones from the dentary and the eventual breakdown of the Meckel’s cartilage during the evolution of mammaliaforms. The middle ear of the Early Cretaceous Liaoconodon hui defines the transitional mammalian middle ear. The Creataceous stem therian Origolestes lii displays the decoupling of hearing and chewing apparatuses and functions. In addition, the discovery of Ambolestes zhoui, an Early Cretaceous eutherian, demonstrates that Sinodelphys, the oldest purported marsupial, is actually a eutherian. The early Eocene haplorrhine primate, Archicebus achilles, resurrects the possibility that Asia was an important stage for early primate evolution. Not only has knowledge concerning these topics been further deepened, but new knowledge has also been acquired concerning Late Cenozoic herbivores and primates in paleomammalogy on the basis of these new discoveries.

Mammalian middle ear mechanics: A review.

The middle ear is part of the ear in all terrestrial vertebrates. It provides an interface between two media, air and fluid. How does it work? In mammals, the middle ear is traditionally described as increasing gain due to Helmholtz’s hydraulic analogy and the lever action of the malleus-incus complex: in effect, an impedance transformer. The conical shape of the eardrum and a frequency-dependent synovial joint function for the ossicles suggest a greater complexity of function than the traditional view. Here we review acoustico-mechanical measurements of middle ear function and the development of middle ear models based on these measurements. We observe that an impedance-matching mechanism (reducing reflection) rather than an impedance transformer (providing gain) best explains experimental findings. We conclude by considering some outstanding questions about middle ear function, recognizing that we are still learning how the middle ear works.

Mutation of foxl1 Results in Reduced Cartilage Markers in a Zebrafish Model of Otosclerosis.

Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor FOXL1 has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for foxl1 in chondrogenesis, osteogenesis, and bone remodelling. We created a foxl1 mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that foxl1 regulates the expression of collagen genes such as collagen type 1 alpha 1a and collagen type 11 alpha 2, and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. foxl1 may also act with other forkhead genes such as foxc1a, as loss of foxl1 in a foxc1a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in foxl1 mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.

Monotreme middle ear is not primitive for Mammalia.

Abstract The study on evolution of the mammalian middle ear has been fueled by continuous discoveries of Mesozoic fossils in the last two decades. Wang et al.1 recently reported a specimen of Vilevolodon diplomylos (IMMNH-PV01699)2 that adds to the increasing knowledge about the auditory apparatus of ‘haramiyidans’, an extinct Mesozoic group of mammaliaforms. The authors hypothesized that a middle ear with a monotreme-like incus and malleus and incudomallear articulation was primitive for mammals, which challenges the convention that the monotreme middle ear is specialized3 or autapomorphic4 in mammals. We raise concerns about terminology and identification of the incus presented by Wang et al. and show that their analysis does not support their hypothesis; instead, it supports the one by Mao et al.5,6.

Uncovering the secreted signals and transcription factors regulating the development of mammalian middle ear ossicles

The mammalian middle ear comprises a chain of ossicles, the malleus, incus, and stapes that act as an impedance matching device during the transmission of sound from the tympanic membrane to the inner ear. These ossicles are derived from cranial neural crest cells that undergo endochondral ossification and subsequently differentiate into their final functional forms. Defects that occur during middle ear development can result in conductive hearing loss. In this review, we summarize studies describing the crucial roles played by signaling molecules such as sonic hedgehog, bone morphogenetic proteins, fibroblast growth factors, notch ligands, and chemokines during the differentiation of neural crest into the middle ear ossicles. In addition to these cell-extrinsic signals, we also discuss studies on the function of transcription factor genes such as Foxi3, Tbx1, Bapx1, Pou3f4, and Gsc in regulating the development and morphology of the middle ear ossicles.

Exploring ancestral phenotypes and evolutionary development of the mammalian middle ear based on Early Cretaceous Jehol mammals.

We report a new Cretaceous multituberculate mammal with 3D auditory bones preserved. Along with other fossil and extant mammals, the unequivocal auditory bones display features potentially representing ancestral phenotypes of the mammalian middle ear. These phenotypes show that the ectotympanic and the malleus-incus complex changed notably during their retreating from the dentary at various evolutionary stages and suggest convergent evolution of some features to extant mammals. In contrast, the incudomalleolar joint was conservative in having a braced hinge configuration, which narrows the morphological gap between the quadroarticular jaw joint of non-mammalian cynodonts and the incudomalleolar articulations of extant mammals. The saddle-shaped and abutting malleus-incus complexes in therians and monotremes, respectively, could have evolved from the braced hinge joint independently. The evolutionary changes recorded in the Mesozoic mammals are largely consistent with the middle ear morphogenesis during the ontogeny of extant mammals, supporting the relation between evolution and development.

Making a mammalian ear. Modular decoupling of the mammalian middle ear and jaw discovered in a new species of Cretaceous stem therian mammals

Evolution of the definitive mammalian middle ear (DMME) as a textbook example in vertebrate evolution has been extensively studied during the last 200 years. Fossils provide the direct evidence on evolutionary stages of the DMME, but because of delicacy of the miniscule ossicles, unequivocal evidence about them has always been rare. Recent work on a stem therian mammal (124 million years old) shows presence of the surangular bone in the basal mammals as a primitive feature and potentially retained in the embryonic stage of some extant mammals. The work also proposed that the DMME and mammalian jaw evolved in a modular fashion. It started as a highly integrated complex in structures and functions, the two modules were regulated by similar developmental genetic mechanisms and eventually decoupled under natural selection so that the physical constraint the two modules imposed on each other was removed, allowing future improvement of each module for better function.

CXCL12 is required for stirrup-shaped stapes formation during mammalian middle ear development.

The mammalian middle ear comprises a chain of three ossicles-the malleus, incus, and stapes-each of which has a unique morphology for efficiently transmitting sound information. In particular, the stapes, which is attached to the inner ear, is stirrup-shaped with a head and base connected by two crural arches, forming the stapedial foramen, through which the stapedial artery passes. However, how the stapes acquires this critical stirrup shape for association with the stapedial artery during development is not clear. C-X-C motif chemokine ligand 12 (CXCL12) is a chemoattractant essential for cellular movement and angiogenesis. In Cxcl12 -/- embryos, migration of neural crest cells into the prospective middle ear regions and their mesenchymal condensation to form the three ossicles proceed normally in correct alignment with each other and the inner ear. However, in the absence of CXCL12, the stapes loses its stirrup shape and instead exhibits a columnar shape lacking the crural arches and central hole. In addition, although the stapedial artery initially forms during early mesenchymal condensation of the stapes, it degenerates without CXCL12 function. CXCL12 plays an essential role in establishing the stirrup-shaped architecture of the stapes, possibly by maintaining the stapedial foramen and stapedial artery throughout development.

Eat and listen-how chewing and hearing evolved.

Mammalian middle ear bones separated from the jaw of vertebrate ancestors

Cretaceous fossil reveals a new pattern in mammalian middle ear evolution.

The evolution of the mammalian middle ear is thought to provide an example of 'recapitulation'-the theory that the present embryological development of a species reflects its evolutionary history. Accumulating data from both developmental biology and palaeontology have suggested that the transformation of post-dentary jaw elements into cranial ear bones occurred several times in mammals1,2. In addition, well-preserved fossils have revealed transitional stages in the evolution of the mammalian middle ear1,3,4. But questions remain concerning middle-ear evolution, such as how and why the post-dentary unit became completely detached from the dentary bone in different clades of mammaliaforms. Here we report a definitive mammalian middle ear preserved in an eobaatarid multituberculate mammal, with complete post-dentary elements that are well-preserved and detached from the dentary bones. The specimen reveals the transformation of the surangular jaw bone from an independent element into part of the malleus of the middle ear, and the presence of a restricted contact between the columelliform stapes and the flat incus. We propose that the malleus-incus joint is dichotomic in mammaliaforms, with the two bones connecting in either an abutting or an interlocking arrangement, reflecting the evolutionary divergence of the dentary-squamosal joint4. In our phylogenetic analysis, acquisition of the definitive mammalian middle ear in allotherians such as this specimen was independent of that in monotremes and therians. Our findings suggest that the co-evolution of the primary and secondary jaw joints in allotherians was an evolutionary adaptation allowing feeding with unique palinal (longitudinal and backwards) chewing. Thus, the evolution of the allotherian auditory apparatus was probably triggered by the functional requirements of the feeding apparatus.

Disconnecting bones within the jaw-otic network modules underlies mammalian middle ear evolution.

The origin of the mammalian middle ear ossicles from the craniomandibular articulation of their synapsid ancestors is a key event in the evolution of vertebrates. The richness of the fossil record and the multitude of developmental studies have provided a stepwise reconstruction of this evolutionary innovation, highlighting the homology between the quadrate, articular, pre-articular and angular bones of early synapsids with the incus, malleus, gonial and ectotympanic bones of derived mammals, respectively. There are several aspects involved in this functional exaptation: (i) an increase of the masticatory musculature; (ii) the separation of the quadrate bone from the cranium; and (iii) the disconnection of the post-dentary bones from the dentary. Here, we compared the jaw-otic complex for 43 synapsid taxa using anatomical network analysis, showing that the disconnection of mandibular bones was a key step in the mammalian middle ear evolution, changing the skull anatomical modularity concomitant to the acquisition of new functions. Furthermore, our analysis allows the identification of three types of anatomical modules evolving through five evolutionary stages during the anatomical transformation of the jawbones into middle ear bones, with the ossification and degradation of Meckel's cartilage in mammals as the key ontogenetic event leading the change of anatomical modularity.

A requirement for Fgfr2 in middle ear development.

The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain-of-function disorders are clinically characterized, those in the FGFR2 loss-of-function disorder lacrimo-auriculo-dento-digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra-articular ligaments of the incudomalleal joint is derived from Scx-expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome.

Hox-A2 protein expression in mouse embryo middle ear ossicles

The origin of the mammalian middle ear ossicles from mandibular and hyoid pharyngeal arches remains controversial and discussed. Two adverse theories are proposed. The first claims that malleus and incus derive from the Meckel's cartilage of the mandibular arch, and stapes from Reichert's cartilage of the hyoid arch. The second postulates that handle of malleus and long process of the incus are derived from the second arch as well as the stapes. Contradictory analyses support alternatively each theory without any experimental evidence. In order to bring new data, we analyzed by immunohistochemistry the expression of Hox-A2 protein in ossicular anlagen in E11 to 13 mouse embryos. HOXA2 gene is known to be expressed in second arch cells and to be absent from mandibular arch derivatives. Surprisingly, Hox-A2 protein was present in all ossicular primordia, as well in Reichert's cartilage. Meckel's cartilage was free of staining. Unlabeled cells were also present in ossicular blastemata. These results suggest that ossicular condensations could arise from mixed cell populations originated in both mandibular and hyoid pharyngeal arches. However, we cannot exclude that diffuse Hox-A2 immunoreactivity could correspond to a secondary expression in craniofacial mesenchyme independently from the branchial origin of cells.

A Functional Perspective on the Evolution of the Cochlea.

This review summarizes paleontological data as well as studies on the morphology, function, and molecular evolution of the cochlea of living mammals (monotremes, marsupials, and placentals). The most parsimonious scenario is an early evolution of the characteristic organ of Corti, with inner and outer hair cells and nascent electromotility. Most remaining unique features, such as loss of the lagenar macula, coiling of the cochlea, and bony laminae supporting the basilar membrane, arose later, after the separation of the monotreme lineage, but before marsupial and placental mammals diverged. The question of when hearing sensitivity first extended into the ultrasonic range (defined here as >20 kHz) remains speculative, not least because of the late appearance of the definitive mammalian middle ear. The last significant change was optimizing the operating voltage range of prestin, and thus the efficiency of the outer hair cells' amplifying action, in the placental lineage only.

The role of miniaturization in the evolution of the mammalian jaw and middle ear.

The evolution of the mammalian jaw is one of the most important innovations in vertebrate history, and underpins the exceptional radiation and diversification of mammals over the last 220 million years1,2. In particular, the transformation of the mandible into a single tooth-bearing bone and the emergence of a novel jaw joint-while incorporating some of the ancestral jaw bones into the mammalian middle ear-is often cited as a classic example of the repurposing of morphological structures3,4. Although it is remarkably well-documented in the fossil record, the evolution of the mammalian jaw still poses the paradox of how the bones of the ancestral jaw joint could function both as a joint hinge for powerful load-bearing mastication and as a mandibular middle ear that was delicate enough for hearing. Here we use digital reconstructions, computational modelling and biomechanical analyses to demonstrate that the miniaturization of the early mammalian jaw was the primary driver for the transformation of the jaw joint. We show that there is no evidence for a concurrent reduction in jaw-joint stress and increase in bite force in key non-mammaliaform taxa in the cynodont-mammaliaform transition, as previously thought5-8. Although a shift in the recruitment of the jaw musculature occurred during the evolution of modern mammals, the optimization of mandibular function to increase bite force while reducing joint loads did not occur until after the emergence of the neomorphic mammalian jaw joint. This suggests that miniaturization provided a selective regime for the evolution of the mammalian jaw joint, followed by the integration of the postdentary bones into the mammalian middle ear.

Human ossicular-joint flexibility transforms the peak amplitude and width of impulsive acoustic stimuli.

The role of the ossicular joints in the mammalian middle ear is still debated. This work tests the hypothesis that the two synovial joints filter potentially damaging impulsive stimuli by transforming both the peak amplitude and width of these impulses before they reach the cochlea. The three-dimensional (3D) velocity along the ossicular chain in unaltered cadaveric human temporal bones (N = 9), stimulated with acoustic impulses, is measured in the time domain using a Polytec (Waldbronn, Germany) CLV-3D laser Doppler vibrometer. The measurements are repeated after fusing one or both of the ossicular joints with dental cement. Sound transmission is characterized by measuring the amplitude, width, and delay of the impulsive velocity profile as it travels from the eardrum to the cochlea. On average, fusing both ossicular joints causes the stapes velocity amplitude and width to change by a factor of 1.77 (p = 0.0057) and 0.78 (p = 0.011), respectively. Fusing just the incudomalleolar joint has a larger effect on amplitude (a factor of 2.37), while fusing just the incudostapedial joint decreases the stapes velocity on average. The 3D motion of the ossicles is altered by fusing the joints. Finally, the ability of current computational models to predict this behavior is also evaluated.

Development of the Human Incus With Special Reference to the Detachment From the Chondrocranium to be Transferred into the Middle Ear.

The mammalian middle ear represents one of the most fundamental features defining this class of vertebrates. However, the origin and the developmental process of the incus in the human remains controversial. The present study seeks to demonstrate all the steps of development and integration of the incus within the middle ear. We examined histological sections of 55 human embryos and fetuses at 6 to 13 weeks of development. At 6 weeks of development (16 Carnegie Stage), the incus anlage was found at the cranial end of the first pharyngeal arch. At this stage, each of the three anlagen of the ossicles in the middle ear were independent in different locations. At Carnegie Stage 17 a homogeneous interzone clearly defined the incus and malleus anlagen. The cranial end of the incus was located very close to the otic capsule. At 7 and 8 weeks was characterized by the short limb of the incus connecting with the otic capsule. At 9 weeks was characterized by an initial disconnection of the incus from the otic capsule. At 13 weeks, a cavity appeared between the otic capsule and incus. Our results provide significant evidence that the human incus developed from the first pharyngeal arch but independently from Meckel's cartilage. Also, during development, the incus was connected with the otic capsule, and then it was detached definitively. The development of the incus in humans provides evidence that this ossicle is homologous to the quadrate. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc.

Expression, Distribution, and Role of C-Type Lectin Receptors in the Human and Animal Middle Ear and Eustachian Tube: A Review.

Otitis media (OM) is a group of inflammatory diseases of the middle ear (ME), regardless of cause or pathological mechanism. Among the molecular biological studies assessing the pathology of OM are investigations into the expression of C-type lectin receptors (CLR) in the ME and Eustachian tube (ET). To date, nine studies have evaluated CLR expression in the ME and ET. The expression of individual CLRs in mammalian ME and ET varies by species and model of OM. Assessments have shown that the patterns of CLR expression in the ME and ET vary; that CLR expression may vary by type of OM; and that the distribution and levels of expression of CLRs may depend on the presence or absence of inflammation, with variations even within the same species and same tissue. Infection of the ME and ET with various pathogens is a common cause of all types of OM, with host responses to pathogens mediated initially by the innate immune system. CLRs are important factors in the innate immune system because they act as both adhesion molecules and as pathogen recognition receptors. The expression of CLRs in OM tissues suggests that CLRs are associated with the pathogenesis of various types of OM.