Transcription factor hierarchies underlying the formation of hair cells versus electroreceptors in the lateral line

我们的听觉，以及我们用来保持平衡的信息，来自于内耳特殊感觉“毛细胞”上的微小“毛发”的运动，这是对内耳内由振动（声音）和头部运动（平衡）引起的流体运动的反应。我们出生时每只耳朵上只有几万个这样的毛细胞，而且它们不能再生：它们可能会因衰老、暴露在嘈杂的噪音中，以及在接受一些抗生素和化疗药物治疗后死亡。虽然哺乳动物的毛细胞不能再生，但鸟类、两栖动物和鱼类的毛细胞可以再生，因此了解这些物种毛细胞的发育和再生是非常有趣的。在鱼类和两栖动物中，毛细胞不仅存在于哺乳动物的内耳中，而且还存在于身体表面，这些毛细胞聚集在被称为神经鞘的微小感觉器官中，它们在头部和身体上以特有的线条排列。这些“侧线”毛细胞就像内耳中的毛细胞一样，但它们检测动物周围局部的水流（而不是内耳内的液体流动）。这些信息用于寻找猎物和探测捕食者，并有助于例如鱼群行为。侧线毛细胞在胚胎时期从“侧线基体”发育而来：头部增厚的皮肤斑块。在斑马鱼中，几乎所有侧线毛细胞发育和再生研究的模型，侧线基板在头部和躯干上成行移动，并在其尾迹中沉积机械感觉器官。然而，专注于单一物种可能会限制我们对如何控制侧线毛细胞发育的理解，因为斑马鱼可能已经进化出了一些物种特有的特性，而且因为这个物种，像大多数现代“硬骨鱼”（“多骨”）鱼（还有青蛙，另一种常用的水生脊椎动物实验室模型）一样，缺少大多数其他水生脊椎动物群体中存在的完整的第二套侧线器官。壶腹器官，包含电感受器，可以探测水中动物周围的弱电场。电感应，一种真正的“第六感”，用于寻找猎物（例如，鲨鱼可以通过周围的弱电场探测到埋在沙子里的比目鱼），用于定位（例如，相对于地球磁场进行长距离迁移），在某些物种中，用于交流。在具有壶腹器官和神经鞘的物种中，如鲨鱼，“原始”硬骨鱼，如鲟鱼，以及水生蝾螈，如美西螈，这两种类型的感觉器官都是从侧线基板形成的，这些基板在头部上方拉长（而不是迁移）形成脊，最终断裂，神经鞘在每个脊的中心形成，壶腹器官在两侧形成。这项拨款提案中的实验旨在了解毛细胞与电感受器形成的重要基因，使用小鲟（一种鲟鱼）作为模型系统，我们每年可以从中获得数千个胚胎。通过这种方法获得的新视角将使我们对毛细胞发育和脊椎动物感觉细胞类型多样化的机制有更深入的了解。

Our sense of hearing, and the information we use for balance, results from the movement of tiny "hairs" on specialised sensory "hair cells" in our inner ears, in response to fluid motion within the inner ear caused by vibrations (for sound) and head movement (for balance). We are born with only a few tens of thousands of these hair cells in each ear and they do not regenerate: they can die through ageing, exposure to loud noise, and after treatment with some antibiotics and chemotherapy drugs. Although mammalian hair cells do not regenerate, hair cells in birds, amphibians and fish can, so there is a great deal of interest in understanding the development and regeneration of hair cells in these species. In fish and amphibians, hair cells are found not just inside the inner ear as in mammals, but also on the body surface, collected in tiny sense organs called neuromasts, which are arranged in characteristic lines over the head and body. These "lateral line" hair cells are just like the ones found in the inner ear, but detect local water flow around the animal (rather than fluid flow within the inner ear). The information is used for finding prey and detecting predators, and contributes to e.g. schooling behaviour. Lateral line hair cells develop embryonically from "lateral line placodes": patches of thickened skin on the head. In zebrafish, the model for almost all research on lateral line hair cell development and regeneration, lateral line placodes migrate in lines over the head and trunk, depositing mechanosensory organs in their wake. However, focusing on a single species potentially limits our understanding of how the development of lateral line hair cells is controlled, both because zebrafish may have evolved some species-specific peculiarities, and because this species, like most such modern "teleost" ("bony") fish (and also frogs, the other commonly used aquatic vertebrate lab model), is missing an entire second set of lateral line organs present in most other aquatic vertebrate groups: ampullary organs, which contain electroreceptors that detect the weak electric fields that surround animals in water. Electroreception, a true "sixth sense", is used for finding prey (for example, a shark can detect a flounder buried in the sand by virtue of the weak electric field surrounding it), for orientation (e.g. for long distance migration relative to the earth's magnetic field) and, in some species, for communication. In species with ampullary organs as well as neuromasts, like sharks, "primitive" bony fishes like sturgeons, and aquatic salamanders such as the axolotl, both types of sense organ form from lateral line placodes that elongate (as opposed to migrate) over the head to form ridges, which eventually fragment, with neuromasts forming in the centre of each ridge and ampullary organs forming on the flanks.The experiments in this grant proposal are aimed at understanding the genes important for the formation of hair cells versus electroreceptors, using the sterlet (a sturgeon) as the model system, from which we can obtain thousands of embryos each year. The fresh perspectives gained through this approach will give us a greater understanding of the mechanisms underlying hair cell development and vertebrate sensory cell type diversification.