Phoenix is required for mechanosensory hair cell regeneration in the zebrafish lateral line.
Phoenix is required for mechanosensory hair cell regeneration in the zebrafish lateral line.
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DOI：
10.1371/journal.pgen.1000455
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发表时间：
2009-04
期刊：
影响因子：
4.5
通讯作者：
Burgess SM
中科院分区：
文献类型：
--
作者：
Behra M;Bradsher J;Sougrat R;Gallardo V;Allende ML;Burgess SM
在人类中，毛细胞的缺失或不可逆转的丧失是后天和先天性听力障碍的主要原因。毛细胞是耳蜗中的感觉机械感受器。在内耳的听觉和前庭神经上皮细胞中，毛细胞伴随着另一种称为支持细胞的细胞。这第二个细胞群被描述为具有干细胞样特性，允许在所有脊椎动物的胚胎和幼体/胎儿发育期间进行有效的毛细胞替换。然而，哺乳动物在出生后失去了大部分内耳神经上皮细胞的再生能力。值得注意的是，爬行动物、鸟类、两栖动物和鱼类的不同之处在于它们可以在整个生命周期内再生毛细胞。两栖动物和鱼类的侧线是一个额外的感觉器官，用于探测水的运动，由神经上皮片组成，称为神经肥大。这些细胞在超微结构上类似于内耳的神经上皮细胞，它们共享各种分子标记的表达。我们研究了斑马鱼幼体侧线毛细胞的再生过程，斑马鱼幼体携带逆转录病毒整合到以前未描述的基因Phoenix(Pho)中。凤凰突变体幼虫发育正常，侧线形态完整。然而，在用铜或新霉素消融毛细胞后，它们在pho突变体中的再生严重受损。我们发现，在毛细胞受损后，支持细胞的增殖明显减少，这与再生的凤凰突变神经肥大中新形成的毛细胞的减少有关。与表型相关的逆转录病毒整合是在一个新的基因中进行的，该基因没有已知的同源物，显示在神经肥大支持细胞中高表达。虽然它在侧线早期发育中的作用仍有待解决，但在后期幼虫阶段，菲尼克斯定义了一类与毛细胞再生有关的新蛋白质。通过对斑马鱼再生缺陷突变的筛选，我们鉴定了一个斑马鱼突变系，该突变系在一个高度特异的再生过程中缺失，即侧线毛细胞的更新。虽然这个器官是鱼类和两栖动物特有的，但它包含的机械感觉细胞(毛细胞)基本上与所有脊椎动物的耳朵中用于声音和平衡检测的机械感觉细胞相同。哺乳动物是一种不同寻常的脊椎动物，因为它们在受到声音或化学物质的破坏后，已经失去了再生功能毛细胞的能力。所有其他脊椎动物在受损后仍具有再生毛细胞的能力，但这一过程在分子水平上还没有被很好地理解。与菲尼克斯突变相关的逆转录病毒插入属于一个新的基因家族类别，这是毛细胞损伤后支持细胞进入有丝分裂所特别需要的。这种突变特别不寻常的是，它似乎不会影响正常的发育和分化途径，但似乎只会影响细胞分化后的再生。
In humans, the absence or irreversible loss of hair cells, the sensory mechanoreceptors in the cochlea, accounts for a large majority of acquired and congenital hearing disorders. In the auditory and vestibular neuroepithelia of the inner ear, hair cells are accompanied by another cell type called supporting cells. This second cell population has been described as having stem cell-like properties, allowing efficient hair cell replacement during embryonic and larval/fetal development of all vertebrates. However, mammals lose their regenerative capacity in most inner ear neuroepithelia in postnatal life. Remarkably, reptiles, birds, amphibians, and fish are different in that they can regenerate hair cells throughout their lifespan. The lateral line in amphibians and in fish is an additional sensory organ, which is used to detect water movements and is comprised of neuroepithelial patches, called neuromasts. These are similar in ultra-structure to the inner ear's neuroepithelia and they share the expression of various molecular markers. We examined the regeneration process in hair cells of the lateral line of zebrafish larvae carrying a retroviral integration in a previously uncharacterized gene, phoenix (pho). Phoenix mutant larvae develop normally and display a morphologically intact lateral line. However, after ablation of hair cells with copper or neomycin, their regeneration in pho mutants is severely impaired. We show that proliferation in the supporting cells is strongly decreased after damage to hair cells and correlates with the reduction of newly formed hair cells in the regenerating phoenix mutant neuromasts. The retroviral integration linked to the phenotype is in a novel gene with no known homologs showing high expression in neuromast supporting cells. Whereas its role during early development of the lateral line remains to be addressed, in later larval stages phoenix defines a new class of proteins implicated in hair cell regeneration. By screening for regeneration deficient zebrafish mutations, we identified a zebrafish mutant line deficient in a highly specific regeneration process, the renewal of hair cells in the lateral line. Although this organ is specific to fish and amphibians, it contains essentially the same mechanosensory cells (the hair cells) that function in the ear for sound and balance detection in all vertebrates. Mammals are unusual vertebrates in that they have lost the ability to regenerate functional hair cells after damage by sound or chemical exposure. All other vertebrates retain their ability to regenerate their hair cells after damage, but this process is not well understood at the molecular level. The retroviral insertion linked to the phoenix mutation is in a new gene family class that is specifically required for the supporting cells to enter into mitosis after hair cell damage. What is particularly unusual about this mutation is that it appears not to affect the normal development and differentiation pathways, but only seems to affect the cells' post-differentiation regeneration.
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DOI：
10.1007/s10162-002-3022-x
发表时间：
2003-06-01
影响因子：
2.4
作者：
Harris, JA;Cheng, AG;Rubel, EW
通讯作者：
Rubel, EW
影响因子：
2.5
作者：
CORWIN, JT
通讯作者：
CORWIN, JT
影响因子：
2.8
作者：
EPSTEIN, JE;COTANCHE, DA
通讯作者：
COTANCHE, DA
影响因子：
56.9
作者：
CORWIN, JT;COTANCHE, DA
通讯作者：
COTANCHE, DA
影响因子：
2.6
作者：
Gompel, N;Cubedo, N;Ghysen, A
通讯作者：
Ghysen, A