Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry Oral and Craniofacial Sciences, King's College London, London, United Kingdom.
Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.
Elife. 2023 Aug 4;12:e86233. doi: 10.7554/eLife.86233.
In vertebrates with elongated auditory organs, mechanosensory hair cells (HCs) are organised such that complex sounds are broken down into their component frequencies along a proximal-to-distal long (tonotopic) axis. Acquisition of unique morphologies at the appropriate position along the chick cochlea, the basilar papilla, requires that nascent HCs determine their tonotopic positions during development. The complex signalling within the auditory organ between a developing HC and its local niche along the cochlea is poorly understood. Using a combination of live imaging and NAD(P)H fluorescence lifetime imaging microscopy, we reveal that there is a gradient in the cellular balance between glycolysis and the pentose phosphate pathway in developing HCs along the tonotopic axis. Perturbing this balance by inhibiting different branches of cytosolic glucose catabolism disrupts developmental morphogen signalling and abolishes the normal tonotopic gradient in HC morphology. These findings highlight a causal link between graded morphogen signalling and metabolic reprogramming in specifying the tonotopic identity of developing HCs.
在具有长听觉器官的脊椎动物中，机械感觉毛细胞 (HCs) 沿着从近端到远端的长（音位）轴排列，使得复杂的声音被分解为其组成频率。雏鸡耳蜗基底乳头中新生 HCs 要在适当的位置获得独特的形态，这需要它们在发育过程中确定其音位位置。在听觉器官中，发育中的 HC 与其在耳蜗上的局部小生境之间的复杂信号传递机制还知之甚少。我们使用活体成像和 NAD(P)H 荧光寿命成像显微镜的组合，揭示了在音位轴上发育中的 HCs 中，糖酵解和戊糖磷酸途径之间的细胞平衡存在梯度。通过抑制细胞质葡萄糖分解代谢的不同分支来破坏这种平衡，会破坏发育形态发生素信号，并消除 HC 形态的正常音位梯度。这些发现强调了分级形态发生素信号和代谢重编程之间的因果关系，以指定发育中的 HCs 的音位身份。
