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Role of the cytokine Macrophage Migration Inhibitory Factor (MIF) in inner ear neuronal and sensory cell development.

机译：细胞因子巨噬细胞迁移抑制因子（MIF）在内耳神经元和感觉细胞发育中的作用。

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摘要

Spiral ganglion neuron (SGN) loss, either dependent or independent of sensory hair cell (HC) loss, is a major cause of deafness, particularly in the ageing population. Cochlear implants (CI) are presently the only known "cure" for many forms of deafness. Nevertheless, successful function of a CI depends on the preservation of SGNs. In the early developing inner ear, the otocyst secretes a factor called Otocyst Derived Factor (ODF). ODF promotes directional neurite outgrowth and neuronal survival of the statoacoustic ganglion (SAG), the precursor of the auditory portion of the SAG that eventually forms the SG. Cytokine arrays and proteomic studies demonstrated that the bioactive components of ODF include Macrophage Migration Inhibitory Factor (MIF), which has been described as "pleiotropic" cytokine because of its multiple roles, including roles in the immune system and in neuronal development and regeneration. Based on its known roles and our preliminary data, we hypothesized that MIF plays a key instructional role, acting as a neurotrophin, in inner ear development. The goal of this dissertation project is to elucidate the role of MIF in inner ear neuronal development as well as the possibility of using this developmental information to study and to enhance inner ear neuronal regeneration. We found that, at low concentrations (5 pg/ml and 5 ng/ml), recombinant MIF alone supports both mouse and chick SAG directional neurite outgrowth and neuronal survival, and evokes a neuronal phenotype from mouse embryonic stem cells (ESC); at higher concentrations (500 ng/ml), MIF inhibits these functions. We also found that MIF is expressed in supporting cells (SC) of the inner ear and its receptor, CD74 is expressed on both SAG and SGN. In the MIF knock-out (KO) mice, abnormal development of both SC and hair cells (HC) as well as a significant hearing impairment in the high frequency region of the cochlea are seen with concomitant loss of SGN in this region of the cochlea. In addition, we observed that the neurites from SG explants extend directionally in culture toward the wild-type (WT) Organ of Corti (OC), but not in the isolated MIF KO OC. Finally, we found that blockade of either MIF or its receptor with antibody or RNAi respectively suppresses SAG neurite outgrowth and survival. Our study indicates that MIF functions as an essential component of normal inner ear neuronal development and innervation and could potentially be used for SGN retention or re-growth as well as to potentiate the function of a cochlear implant in the injured or diseased mammalian inner ear.
机译：螺旋神经节神经元（SGN）的丢失，无论与感觉毛细胞（HC）的丢失有关或无关，都是导致耳聋的主要原因，尤其是在老年人口中。耳蜗植入物（CI）是目前唯一已知的多种耳聋治疗方法。但是，CI的成功功能取决于SGN的保存。在早期发育的内耳中，耳囊分泌一种称为耳囊衍生因子（ODF）的因子。 ODF促进定向声神经节（SAG）的定向神经突向外生长和神经元存活，SAG是最终形成SG的SAG听觉部分的前体。细胞因子阵列和蛋白质组学研究表明，ODF的生物活性成分包括巨噬细胞迁移抑制因子（MIF），由于其多种作用，包括在免疫系统以及神经元发育和再生中的作用，已被描述为“多效”细胞因子。基于其已知的作用和我们的初步数据，我们假设MIF在内耳发育中起关键的指导作用，作为神经营养蛋白。本研究项目的目的是阐明MIF在内耳神经元发育中的作用，以及利用这种发育信息研究和增强内耳神经元再生的可能性。我们发现，在低浓度（5 pg / ml和5 ng / ml）下，重组MIF单独支持小鼠和雏鸡的SAG定向神经突生长和神经元存活，并引起小鼠胚胎干细胞（ESC）的神经元表型。在较高浓度（500 ng / ml）下，MIF抑制了这些功能。我们还发现，MIF在内耳及其受体的支持细胞（SC）中表达，CD74在SAG和SGN上表达。在MIF基因敲除（KO）小鼠中，SC和毛细胞（HC）的异常发育以及耳蜗高频区域的明显听力障碍均伴随着该耳蜗区域SGN的丧失。 。此外，我们观察到来自SG外植体的神经突在培养中朝着野生型（WT）的Corti（OC）器官定向延伸，但在分离的MIF KO OC中却没有。最后，我们发现用抗体或RNAi阻断MIF或其受体可分别抑制SAG神经突的生长和存活。我们的研究表明，MIF是正常内耳神经元发育和神经支配的重要组成部分，并有可能用于SGN保留或重新生长，以及增强受伤或患病的哺乳动物内耳中的人工耳蜗的功能。

著录项

  • 作者

    Ebisu, Fumi.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Health Sciences Audiology.;Health Sciences General.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 192 p.
  • 总页数 192
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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