Transient retinoic acid signaling confers anterior-posterior polarity to the inner ear

Department of Anatomy, BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, South Korea.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2011; 108(1):161-6. DOI: 10.1073/pnas.1010547108
Source: PubMed


Vertebrate hearing and balance are based in complex asymmetries of inner ear structure. Here, we identify retinoic acid (RA) as an extrinsic signal that acts directly on the ear rudiment to affect its compartmentalization along the anterior-posterior axis. A rostrocaudal wave of RA activity, generated by tissues surrounding the nascent ear, induces distinct responses from anterior and posterior halves of the inner ear rudiment. Prolonged response to RA by posterior otic tissue correlates with Tbx1 transcription and formation of mostly nonsensory inner ear structures. By contrast, anterior otic tissue displays only a brief response to RA and forms neuronal elements and most sensory structures of the inner ear.

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    • "Some additional factors have the potential to improve the potency of induction to hair cells from otic placodal cells. Previous studies have revealed the roles of retinoic acid (RA) [1] and/or Sonic hedgehog (SHH) [3] signaling as inducers of the prosensory fate. In the future, we intend to examine the efficacy of hair cell induction by manipulation of the RA and/or SHH signaling pathway. "
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    ABSTRACT: Disease-specific induced pluripotent stem cells (iPS) cells are expected to contribute to exploring useful tools for studying the pathophysiology of inner ear diseases and to drug discovery for treating inner ear diseases. For this purpose, stable induction methods for the differentiation of human iPS cells into inner ear hair cells are required. In the present study, we examined the efficacy of a simple induction method for inducing the differentiation of human iPS cells into hair cells. The induction of inner ear hair cell-like cells was performed using a stepwise method mimicking inner ear development. Human iPS cells were sequentially transformed into the preplacodal ectoderm, otic placode, and hair cell-like cells. As a first step, preplacodal ectoderm induction, human iPS cells were seeded on a Matrigel-coated plate and cultured in a serum free N2/B27 medium for 8 days according to a previous study that demonstrated spontaneous differentiation of human ES cells into the preplacodal ectoderm. As the second step, the cells after preplacodal ectoderm induction were treated with basic fibroblast growth factor (bFGF) for induction of differentiation into otic-placode-like cells for 15 days. As the final step, cultured cells were incubated in a serum free medium containing Matrigel for 48 days. After preplacodal ectoderm induction, over 90% of cultured cells expressed the genes that express in preplacodal ectoderm. By culture with bFGF, otic placode marker-positive cells were obtained, although their number was limited. Further 48-day culture in serum free media resulted in the induction of hair cell-like cells, which expressed a hair cell marker and had stereocilia bundle-like constructions on their apical surface. Our results indicate that hair cell-like cells are induced from human iPS cells using a simple stepwise method with only bFGF, without the use of xenogeneic cells. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 05/2015; 599. DOI:10.1016/j.neulet.2015.05.032 · 2.03 Impact Factor
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    • "While there is a growing understanding of the molecular pathways involved in patterning the developing inner ear, there are seemingly contradictory findings across species (Whitfield and Hammond, 2007; Groves and Fekete, 2012). In chick and mice, RA is involved in anterior and posterior patterning (Bok et al., 2011). In contrast, A-P patterning in zebrafish depends on two different cell signaling pathways, which is likely the case for Xenopus as well (Hammond and Whitfield, 2011). "
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    ABSTRACT: Background: The inner ear develops from an ectodermal thickening known as the otic placode into a complex structure that is asymmetrical along both the anterior-posterior (A-P) and dorsal-ventral (D-V) axes. Embryological manipulations in Xenopus allow us to test regenerative potential along specific axes and timing of axis determination. We explore the role of Wnt signaling with gain and loss of function experiments. Results: In contrast to A or P half ablations, D or V half ablations almost never result in mirror duplications or normal ears. Instead there is a loss of structures, especially those associated with the ablated region. Rotation experiments inverting the D-V axis reveal that it is determined by stage 24-26 which is just before expression of the dorsal otic marker Wnt3a. Conditional blocking of canonical Wnt signaling results in reductions in the number of sensory organs and semicircular canals which could be placed in one of three categories, the most common phenotypes being similar to those seen after dorsal ablations. Conclusions: There is less regenerative potential along the D-V axis. Wnt3a protein alone is sufficient to rescue the severe loss of inner ear structures resulting from dorsal but not ventral half ablations.
    Developmental Dynamics 10/2014; 243(10). DOI:10.1002/dvdy.24116 · 2.38 Impact Factor
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    • "Interestingly, and in support of the idea that the otocyst is polarized by either a concentration gradient of RA or a differential time exposure of anterior and posterior otic epithelia to RA, focal pharmacologic depletion of RA anterior to the otic placode reduces Lfng and NeuroD signals in the anterior otocyst. This suggests that low concentrations or short exposures to RA are required under normal conditions to induce or maintain anterior gene expression and neurogenesis (Bok et al. 2011). "
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    ABSTRACT: The vertebrate inner ear is composed of multiple sensory receptor epithelia, each of which is specialized for detection of sound, gravity, or angular acceleration. Each receptor epithelium contains mechanosensitive hair cells, which are connected to the brainstem by bipolar sensory neurons. Hair cells and their associated neurons are derived from the embryonic rudiment of the inner ear epithelium, but the precise spatial and temporal patterns of their generation, as well as the signals that coordinate these events, have only recently begun to be understood. Gene expression, lineage tracing, and mutant analyses suggest that both neurons and hair cells are generated from a common domain of neural and sensory competence in the embryonic inner ear rudiment. Members of the Shh, Wnt, and FGF families, together with retinoic acid signals, regulate transcription factor genes within the inner ear rudiment to establish the axial identity of the ear and regionalize neurogenic activity. Close-range signaling, such as that of the Notch pathway, specifies the fate of sensory regions and individual cell types. We also describe positive and negative interactions between basic helix-loop-helix and SoxB family transcription factors that specify either neuronal or sensory fates in a context-dependent manner. Finally, we review recent work on inner ear development in zebrafish, which demonstrates that the relative timing of neurogenesis and sensory epithelial formation is not phylogenetically constrained.
    Cell and Tissue Research 06/2014; 359(1). DOI:10.1007/s00441-014-1917-6 · 3.57 Impact Factor
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