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

Ankamreddy, Harinarayana; Bok, Jinwoong; Groves, Andrew K.

doi:10.1002/dvdy.260

Cited by 8 publications

(6 citation statements)

References 132 publications

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“…Here, we report on a foxl1 mutant strain in zebrafish as a potential model of otosclerosis and osteoporosis. Structures in the mammalian middle ear are homologous with the ceratohyal, palatoquadrate, and hyomandibular jaw bones in zebrafish [ 48 , 51 , 52 , 53 , 71 ] and as such, the malformation of these bones leads to the loss of sound conduction in mammals and jaw formation in zebrafish. Despite abundant foxl1 expression in the pharyngeal arches and a delay in cartilage formation and calcification in the jaw, loss of foxl1 does not significantly affect the overall structure of the craniofacial skeleton, consistent with recent reports using strain harboring a foxl1 nonsense mutation [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…We also utilize two previously studied zebrafish forkhead mutants ( foxc1a and foxc1b ) [ 42 , 43 ] in conjunction with a new foxl1 mutant line to examine the importance of foxl1 in the FOX map. As key cartilage/bone developmental and remodelling pathways are conserved between teleosts and mammals [ 4 , 10 , 16 , 31 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ], as well as aspects of the zebrafish jaw being homologous to the middle ear bones of mammals [ 49 , 51 , 52 , 53 ], zebrafish make an excellent model for the study of otosclerosis and osteoporosis [ 54 , 55 , 56 , 57 , 58 ]. We find that while foxl1 regulates the expression of known markers of chondro/osteogenesis, CRISPR-induced mutation of foxl1 in zebrafish only results in a delay in the formation of craniofacial cartilages and subsequent calcification, with no apparent effects on axial skeletal development.…”

Section: Introductionmentioning

confidence: 99%

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

Hawkey-Noble

Pater

Kollipara

et al. 2022

Genes

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hawkey-Noble

Pater

Kollipara

et al. 2022

Genes

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“…Like the cochlea, the vestibule displays a high degree of architectural organization in all its compartments and subregions, with multiple parameters, including dimension, volume, liquid composition, radius of the canal, and vestibular vs. cochlear chambers, constructed to facilitate optimal responses to species-specific directional (gravity and motion displacements) and acoustic (frequency range) features ( 29 , 44 , 59 ). The construction of this diversity involves strict developmental programs that are finely tuned in time and space, and necessary for adaptation to the specific needs of aquatic, terrestrial and aerial species ( 1 – 5 ). Cross-species comparative morphological and molecular analyses of neurosensory epithelia from distantly related species may provide a wealth of information, highlighting essential organ and cell similarities and differences shedding light on the development and functioning of the inner ear suborgans.…”

Section: How Does the Inner Ear Vestibular System Develop And Function?mentioning

confidence: 99%

“…Hearing and balance display tight anatomical and functional links. Both organs originated from a single otic vesicle that develops by the invagination of surface ectoderm adjacent to the developing hindbrain ( 1 – 5 ). However, changes in the needs of species in fluctuating environments have led to species-specific tissue and cellular adaptations.…”

Section: Introductionmentioning

confidence: 99%

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

2022

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The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.

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“…Lastly, we chose to study the Sonic hedgehog (Shh) gene protein distribution in cholesteatoma and control skin tissue. Sonic hedgehog encodes the pharyngeal endoderm and directly controls the early development of the middle ear [ 27 ]. Chiang et al proved that the loss of Shh causes external- and middle -ear pathologies [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Morphopathogenesis of Adult Acquired Cholesteatoma

2023

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Background and Objectives. The aim of this study was to compare the distribution of proliferation markers (Ki-67, NF-κβ), tissue-remodeling factors (MMP-2, MMP-9, TIMP-2, TIMP-4), vascular endothelial growth factor (VEGF), interleukins (IL-1 and IL-10), human beta defensins (HβD-2 and HβD-4) and Sonic hedgehog gene protein in cholesteatoma and control skin. Methods. Nineteen patient cholesteatoma tissues and seven control skin materials from cadavers were included in the study and stained immunohistochemically. Results. Statistically discernible differences were found between the following: the Ki-67 in the matrix and the Ki-67 in the skin epithelium (p = 0.000); the Ki-67 in the perimatrix and the Ki-67 in the connective tissue (p = 0.010); the NF-κβ in the cholesteatoma matrix and the NF-κβ in the epithelium (p = 0.001); the MMP-9 in the matrix and the MMP-9 in the epithelium (p = 0.008); the HβD-2 in the perimatrix and the HβD-2 in the connective tissue (p = 0.004); and the Shh in the cholesteatoma’s perimatrix and the Shh in the skin’s connective tissue (p = 0.000). Conclusion. The elevation of Ki-67 and NF-κβ suggests the induction of cellular proliferation in the cholesteatoma. Intercorrelations between VEGF, NF-κβ and TIMP-2 induce neo-angiogenesis in adult cholesteatoma. The similarity in the expression of IL-1 and IL-10 suggests the dysregulation of the local immune status in cholesteatoma. The overexpression of the Sonic hedgehog gene protein in the cholesteatoma proves the selective local stimulation of perimatrix development.

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

Cited by 8 publications

References 132 publications

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

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

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

Morphopathogenesis of Adult Acquired Cholesteatoma

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