Anteroposterior patterning of the zebrafish ear through Fgf- and Hh-dependent regulation of hmx3a expression
Anteroposterior patterning of the zebrafish ear through Fgf- and Hh-dependent regulation of hmx3a expression
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DOI：
10.1371/journal.pgen.1008051
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发表时间：
2019-04-01
期刊：
影响因子：
4.5
通讯作者：
Whitfield, Tanya T.
中科院分区：
文献类型：
--
作者：
Hartwell, Ryan D.;England, Samantha J.;Whitfield, Tanya T.
在斑马鱼中，FGF和Hh信号分配前部和后部的身份，分别为发展中的耳朵的两极。fgf 3的错误表达或Hh信号传导的抑制导致双前耳，包括hmx 3a的异位表达。为了了解这种双前模式是如何建立的，我们表征了FGF信号获得或Hh信号丢失背景中的转录反应。fgf 3的错误表达导致前耳标记物的快速扩张，随着时间的推移而不断完善，从而产生重复的模式。Hh抑制反应是非常不同的：最初的前后不对称保留，与从头重复的表达域出现后。我们表明，Hmx 3a是所需的正常前耳图案，和耳图案缺陷hmx 3a（-/-）突变体是一个密切的表型fgf 3（-/-）突变体中看到的。然而，hmx 3a功能的丧失或获得都不足以产生全耳复制。使用我们的数据来推断所需的转录调控网络收购耳前身份，我们可以概括的野生型和双前模式的数学model.Author摘要了解信号分子如何传递信息的发展中的器官系统，以及如何通过网络的基因活性解释，是一个关键目标的发育遗传分析。在发育中的斑马鱼内耳中，耳基板的前极和后极之间出现基因表达差异，确保耳朵中的感觉结构在正确的位置发育。如果信号通路被破坏，就会产生镜像耳，发育出两个前极。我们已经使用遗传，药理学和数学建模的方法来破译所需的基因作用的途径，以指定在斑马鱼的耳朵前部结构。基因表达的模式是动态的和可塑的，有两种不同的途径导致形成重复的前结构。hmx 3a基因的表达是对前部信号分子Fgf 3的早期反应，但不足以驱动耳后部异位前部结构的形成。hmx 3a基因编码一种调节其他基因的蛋白质，在人类中，HMX基因的突变会导致影响内耳功能的疾病。我们的工作提供了一个框架，以了解在发展中的内耳早期模式化事件的动态。
In the zebrafish, Fgf and Hh signalling assign anterior and posterior identity, respectively, to the poles of the developing ear. Mis-expression of fgf3 or inhibition of Hh signalling results in double-anterior ears, including ectopic expression of hmx3a. To understand how this double-anterior pattern is established, we characterised transcriptional responses in Fgf gain-of-signalling or Hh loss-of-signalling backgrounds. Mis-expression of fgf3 resulted in rapid expansion of anterior otic markers, refining over time to give the duplicated pattern. Response to Hh inhibition was very different: initial anteroposterior asymmetry was retained, with de novo duplicate expression domains appearing later. We show that Hmx3a is required for normal anterior otic patterning, and that otic patterning defects in hmx3a(-/-) mutants are a close phenocopy to those seen in fgf3(-/-) mutants. However, neither loss nor gain of hmx3a function was sufficient to generate full ear duplications. Using our data to infer a transcriptional regulatory network required for acquisition of otic anterior identity, we can recapitulate both the wild-type and the double-anterior pattern in a mathematical model.Author summary Understanding how signalling molecules impart information to developing organ systems, and how this is interpreted through networks of gene activity, is a key goal of developmental genetic analysis. In the developing zebrafish inner ear, differences in gene expression arise between the anterior and posterior poles of the ear placode, ensuring that sensory structures in the ear develop in their correct positions. If signalling pathways are disrupted, a mirror-image ear can result, developing with two anterior poles. We have used genetic, pharmacological and mathematical modelling approaches to decipher the pathway of gene action required to specify anterior structures in the zebrafish ear. Patterns of gene expression are dynamic and plastic, with two different routes leading to the formation of duplicate anterior structures. Expression of the hmx3a gene is an early response to the anterior signalling molecule Fgf3, but is not sufficient to drive the formation of ectopic anterior structures at the posterior of the ear. The hmx3a gene codes for a protein that regulates other genes, and in humans, mutation of HMX genes results in diseases affecting inner ear function. Our work provides a framework for understanding the dynamics of early patterning events in the developing inner ear.