RA and FGF signalling are required in the zebrafish otic vesicle to pattern and maintain ventral otic identities.
RA and FGF signalling are required in the zebrafish otic vesicle to pattern and maintain ventral otic identities.
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DOI：
10.1371/journal.pgen.1004858
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发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
Whitfield TT
中科院分区：
文献类型：
--
作者：
Maier EC;Whitfield TT
在斑马鱼内耳发育过程中，耳囊腹侧的区域模式建立了与神经源性、感觉性和非神经细胞命运相对应的基因表达区。已知来自周围组织的FGF和视黄酸（RA）信号在耳基板诱导和耳轴模式中具有早期作用，但在耳囊泡（OV）阶段，外部信号信号如何转化为内在模式尚不清楚。FGF和RA信号通路成员在OV内和周围表达，表明在后期模式或维持事件中起重要作用。我们分析了FGF和RA信号在初始前后脑模式发生后的发育阶段的时间需求。我们发现高水平的FGF信号会限制感觉细胞的命运，而低水平的FGF则有利于感觉毛细胞的发育；此外，FGF是促进OV中非神经标记物otx1b表达的必要条件和充分条件。RA信号具有相反的作用：促进感觉命运，限制otx1b的表达和非神经命运的发展。这与早期通过tbx1表达规范非神经命运对RA信号的要求令人惊讶地不同，并突出了斑马鱼中发生在原位和囊泡阶段之间的调节转变。FGF和RA信号在耳神经原性结构域的发育和耳神经母细胞的产生中都是必需的。此外，我们的研究结果表明，FGF和RA信号在前OV的反馈回路中起作用，这对模式优化至关重要。脊椎动物的内耳是一个复杂的三维结构，具有听觉和平衡功能。为了在胚胎中形成一个功能性的耳朵，在正确的时间和正确的位置发育正确的细胞是至关重要的。这些细胞包括检测声音和运动的感觉毛细胞，将感觉信息传递给大脑的神经元，以及结构细胞。我们研究了斑马鱼胚胎发育中的耳朵的模式和维持事件。我们发现两种信号通路，FGF和视黄酸（RA），以拮抗的方式调节发育的感觉毛细胞的数量，以及结构细胞发育所需的关键基因otx1b的表达。然而，这两种信号通路协同作用来调节神经元细胞的出现。我们的数据还表明，FGF和RA信号形成了一个反馈回路，将它们置于调节网络的核心，确保正确的模式在耳朵中维持。FGF和RA信号都被用来产生毛细胞和神经元，用于治疗听力损失的替代疗法。了解FGF和RA信号的作用是此类疗法发展的基础。
During development of the zebrafish inner ear, regional patterning in the ventral half of the otic vesicle establishes zones of gene expression that correspond to neurogenic, sensory and non-neural cell fates. FGF and Retinoic acid (RA) signalling from surrounding tissues are known to have an early role in otic placode induction and otic axial patterning, but how external signalling cues are translated into intrinsic patterning during otic vesicle (OV) stages is not yet understood. FGF and RA signalling pathway members are expressed in and around the OV, suggesting important roles in later patterning or maintenance events. We have analysed the temporal requirement of FGF and RA signalling for otic development at stages after initial anteroposterior patterning has occurred. We show that high level FGF signalling acts to restrict sensory fates, whereas low levels favour sensory hair cell development; in addition, FGF is both required and sufficient to promote the expression of the non-neural marker otx1b in the OV. RA signalling has opposite roles: it promotes sensory fates, and restricts otx1b expression and the development of non-neural fates. This is surprisingly different from the earlier requirement for RA signalling in specification of non-neural fates via tbx1 expression, and highlights the shift in regulation that takes place between otic placode and vesicle stages in zebrafish. Both FGF and RA signalling are required for the development of the otic neurogenic domain and the generation of otic neuroblasts. In addition, our results indicate that FGF and RA signalling act in a feedback loop in the anterior OV, crucial for pattern refinement. The vertebrate inner ear is a complex three-dimensional structure with hearing and balance functions. To form a functional ear in the embryo, it is crucial that the right cells develop at the right time and in the right place. These cells include the sensory hair cells that detect sound and movement, neurons that relay sensory information to the brain, and structural cells. We have investigated patterning and maintenance events in the developing ear of the zebrafish embryo. We show that two signalling pathways, FGF and Retinoic Acid (RA), act in an antagonistic manner to regulate the numbers of sensory hair cells that develop, together with the expression of a key gene, otx1b, required for the development of structural cells. However, the two signalling pathways act in concert to regulate the emergence of neuronal cells. Our data also indicate that FGF and RA signalling form a feedback loop, placing them at the heart of the regulatory network that ensures correct patterning is maintained in the ear. Both FGF and RA signalling are employed to generate hair cells and neurons for replacement therapies to treat hearing loss. Understanding the roles of FGF and RA signalling underpins the development of such therapies.
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