Carlsten J A, Kothary R, Wright D E
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
J Comp Neurol. 2001 Apr 2;432(2):155-68. doi: 10.1002/cne.1094.
We have investigated the fate of different neurotrophin-responsive subpopulations of dorsal root ganglion neurons in dystonia musculorum (dt) mice. These mice have a null mutation in the cytoskeletal linker protein, dystonin. Dystonin is expressed by all sensory neurons and cross links actin filaments, intermediate filaments, and microtubules. The dt mice undergo massive sensory neurodegeneration postnatally and die at around 4 weeks of age. We assessed the surviving and degenerating neuronal populations by comparing the dorsal root ganglion (DRG) neurons and central and peripheral projections in dt mice and wildtype mice. Large, neurofilament-H-positive neurons, many of which are muscle afferents and are neurotrophin-3 (NT-3)-responsive, were severely decreased in number in dt DRGs. The loss of muscle afferents was correlated with a degeneration of muscle spindles in skeletal muscle. Nerve growth factor (NGF)-responsive populations, which were visualized using calcitonin gene-related peptide and p75, appeared qualitatively normal in the lumbar spinal cord, DRG, and hindlimb skin. In contrast, glial cell line-derived neurotrophic factor (GDNF)-responsive populations, which were visualized using the isolectin B-4 and thiamine monophosphatase, were severely diminished in the lumbar spinal cord, DRG, and hindlimb skin. Analysis of NT-3, NGF, and GDNF mRNA levels using semiquantitative reverse transcriptase-polymerase chain reaction revealed normal trophin synthesis in the peripheral targets of dt mice, arguing against decreased trophic synthesis as a possible cause of neuronal degeneration. Thus, the absence of dystonin results in the selective survival of NGF-responsive neurons and the postnatal degeneration of many NT-3- and GDNF-responsive neurons. Our results reveal that the loss of this ubiquitously expressed cytoskeletal linker has diverse effects on sensory subpopulations. Moreover, we show that dystonin is critical for the maintenance of certain DRG neurons, and its function may be related to neurotrophic support.
我们研究了肌张力障碍小鼠（dt）中背根神经节神经元不同神经营养因子反应性亚群的命运。这些小鼠的细胞骨架连接蛋白dystonin存在无效突变。所有感觉神经元均表达dystonin，它能交联肌动蛋白丝、中间丝和微管。dt小鼠出生后会经历大量感觉神经元退变，并在约4周龄时死亡。我们通过比较dt小鼠和野生型小鼠的背根神经节（DRG）神经元以及中枢和外周投射，评估了存活和退变的神经元群体。dt DRG中，大量神经丝-H阳性神经元数量严重减少，其中许多是肌肉传入神经元且对神经营养因子-3（NT-3）有反应。肌肉传入神经元的丧失与骨骼肌中肌梭的退变相关。使用降钙素基因相关肽和p75可视化的神经生长因子（NGF）反应性群体，在腰脊髓、DRG和后肢皮肤中在质量上看起来正常。相比之下，使用异凝集素B-4和硫胺单磷酸酶可视化的胶质细胞源性神经营养因子（GDNF）反应性群体，在腰脊髓、DRG和后肢皮肤中严重减少。使用半定量逆转录聚合酶链反应分析NT-3、NGF和GDNF mRNA水平，结果显示dt小鼠外周靶标中神经营养因子合成正常，这表明神经营养因子合成减少不是神经元退变的可能原因。因此，dystonin的缺失导致NGF反应性神经元的选择性存活以及许多NT-3和GDNF反应性神经元的出生后退变。我们的结果表明，这种普遍表达的细胞骨架连接蛋白的缺失对感觉亚群有多种影响。此外，我们表明dystonin对某些DRG神经元的维持至关重要，其功能可能与神经营养支持有关。
