Severe sensory deficits but normal CNS development in newborn mice lacking TrkB and TrkC tyrosine protein kinase receptors
Severe sensory deficits but normal CNS development in newborn mice lacking TrkB and TrkC tyrosine protein kinase receptors
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DOI：
10.1111/j.1460-9568.1997.tb01372.x
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发表时间：
1997-10-01
影响因子：
3.4
通讯作者：
Barbacid, M
中科院分区：
文献类型：
--
作者：
SilosSantiago, I;Fagan, AM;Barbacid, M
对编码神经营养蛋白及其信号Trk受体的基因携带靶向突变的小鼠的分析提供了有关这些分子在哺乳动物神经系统中所发挥作用的关键信息。在这项研究中，我们产生了TrkB和TrkC酪氨酸激酶受体缺陷的小鼠，以确定这些受体在缺乏代偿机制的情况下的生物学效应。return（-）; trkC（-/-）双突变小鼠以预期的频率出生，表明TrkB和TrkC信号传导不是胚胎存活所必需的。然而，这些双突变小鼠的寿命明显较短，并且比其单突变trkB（-/-）和trkC（-/-）同窝出生的小鼠表现出更严重的感觉缺陷。在trkB（-/-）;trkC（-/-）突变小鼠中观察到的最显著的感觉缺陷是前庭和耳蜗神经节的缺失。有趣的是，尽管这些小鼠完全没有感觉神经支配，但它们却发育出了内耳感觉上皮细胞。对trkB（-/-）;trkC（-/-）突变小鼠的CNS分析显示了形成良好的海马、皮质和丘脑。此外，在这些动物中，几种神经元标记物的表达模式似乎正常。这些观察结果表明，通过TrkB和TrkC受体的神经营养因子信号传导是必不可少的感觉神经节的发展，但是，它并没有发挥重要作用，在胚胎发育过程中的CNS神经元的分化和生存。
Analysis of mice carrying targeted mutations in genes encoding neurotrophins and their signalling Trk receptors has provided critical information regarding the role that these molecules play in the mammalian nervous system. In this study we generated mice defective in both TrkB and TrkC tyrosine kinase receptors to determine the biological effects of these receptors in the absence of compensatory mechanisms. trkB(-/-);trkC(-/-) double-mutant mice were born at the expected frequency, indicating that TrkB and TrkC signalling are not required for embryonic survival. However, these double-mutant mice had a significantly shorter lifespan and displayed more severe sensory defects than their single-mutant trkB(-/-) and trkC(-/-) littermates. The most dramatic sensory deficit observed in trkB(-/-);trkC(-/-) mutant mice was the absence of vestibular and cochlear ganglia. Interestingly, these mice developed inner ear sensory epithelia in spite of the complete absence of sensory innervation. Analysis of the CNS in trkB(-/-);trkC(-/-) mutant mice revealed a well formed hippocampus, cortex and thalamus. Moreover, the pattern of expression of several neuronal markers appeared normal in these animals. These observations suggest that neurotrophin signalling through TrkB and TrkC receptors is essential for the development of sensory ganglia; however, it does not play a major role in the differentiation and survival of CNS neurons during embryonic development.