Signaling regulating inner ear development: Cell fate determination, patterning, morphogenesis, and defects

Abstract

The membranous labyrinth of the inner ear is a highly complex organ that detects sound and balance. Developmental defects in the inner ear cause congenital hearing loss and balance disorders. The membranous labyrinth consists of three semicircular ducts, the utricle, saccule, and endolymphatic ducts, and the cochlear duct. These complex structures develop from the simple otic placode, which is established in the cranial ectoderm adjacent to the neural crest at the level of the hindbrain at the early neurula stage. During development, the otic placode invaginates to form the otic vesicle, which subsequently gives rise to neurons for the vestibulocochlear ganglion, the non-sensory and sensory epithelia of the membranous labyrinth that includes three ampullary crests, two maculae, and the organ of Corti. Combined paracrine and autocrine signals including fibroblast growth factor, Wnt, retinoic acid, hedgehog, and bone morphogenetic protein regulate fate determination, axis formation, and morphogenesis in the developing inner ear. Juxtacrine signals mediated by Notch pathways play a role in establishing the sensory epithelium, which consists of mechanosensory hair cells and supporting cells. The highly differentiated organ of Corti, which consists of uniformly oriented inner/outer hair cells and specific supporting cells, develops during fetal development. Developmental alterations/arrest causes congenital malformations in the inner ear in a spatiotemporal-restricted manner. A clearer understanding of the mechanisms underlying inner ear development is important not only for the management of patients with congenital inner ear malformations, but also for the development of regenerative therapy for impaired function.

Survival of human embryonic stem cells implanted in the guinea pig auditory epithelium

“…Although the fate of differentiated cells in this study was not systematically evaluated, the survival of hundreds of cells offers the possibility that they could be subsequently guided to differentiate through successive developmental milestones by supplying exogenous factors, via timed drug release or cannulation. Cues can be taken from current protocols for in vitro reprogramming strategies and would necessarily include manipulation of BMP signaling to produce non-neural ectoderm and subsequent treatment with FGF and Wnt to influence otic differentiation32. Introduction of the appropriate exogenous factors will likely need to occur shortly after the surviving cells are stabilized in the scala media.…”

Cyp1B1 expression patterns in the developing chick inner ear

“…RA directly controls the morphogenesis and specification mechanisms during the development of vertebrate inner ears, mainly by means of RA‐synthesizing RALDH enzymes (reviewed in References ; see also Reference ). In the developing mouse inner ear, Raldh1‐3 genes have restricted and dynamic expression patterns with overlapping domains .…”

“…It is well accepted that RA generated from the underlying mesenchyme by RALDH activities participate directly in the specification of the neural tube along its anterior‐to‐posterior and dorsal‐to‐ventral axes . Similarly, RA from the periotic mesenchyme may control the regionalization of the developing otic epithelium in a stage‐dependent manner . In the chick, Raldh2 is expressed in the mesoderm caudal to the otic placode, and an appropriate spatial and temporal concentration of the diffusible RA is necessary for the correct specification of the anterior‐posterior axis of the developing otic anlagen .…”

“…20,39,42,51,54,[110][111][112][113] Similarly, RA from the periotic mesenchyme may control the regionalization of the developing otic epithelium in a stage-dependent manner. 9,10,15,29,107,[114][115][116][117] In the chick, Raldh2 is expressed in the mesoderm caudal to the otic placode, and an appropriate spatial and temporal concentration of the diffusible RA is necessary for the correct specification of the anteriorposterior axis of the developing otic anlagen. 114 In this sense, it has been suggested that the CYP1B1-mediated RA synthesis in the paraxial mesoderm could also participate directly in the dorsal-to-ventral specification of the developing neural tube in a paracrine manner.…”

“…These signaling molecules act in a concentration-dependent manner controlling the expression of regulatory genes. [16][17][18][19][20][21] These spatial and temporal dynamic interactions also govern the morphogenetic and specification events occurring during the development of vertebrate inner ears (Bok et al, among others 3,4,9,10,12,15,[22][23][24][25][26][27][28][29][30][31][32].…”