BDNF gene replacement reveals multiple mechanisms for establishing neurotrophin specificity during sensory nervous system development
BDNF gene replacement reveals multiple mechanisms for establishing neurotrophin specificity during sensory nervous system development
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DOI：
10.1242/dev.00378
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发表时间：
2003-04-01
期刊：
影响因子：
4.6
通讯作者：
Ernfors, P
中科院分区：
文献类型：
--
作者：
Agerman, K;Hjerling-Leffler, J;Ernfors, P
神经营养因子在周围神经系统发育过程中具有多种功能，如控制神经元存活、靶神经支配和突触发生。神经营养因子特异性归因于Trk酪氨酸激酶受体在不同神经元亚群中的选择性表达。然而，尽管在许多感觉神经节中TrkB和TrkC的重叠表达，脑源性神经营养因子（BDNF）和神经营养因子3（NT 3）无效突变小鼠显示神经元亚群的选择性损失。在本研究中，我们已经取代了编码部分的BDNF基因在小鼠与NT 3（BDNF NT 3/NT 3），以分析的特异性和选择性BDNF和NT 3在发育过程中的作用。对BDNFNT 3/NT 3小鼠的分析显示，NT 3在不同感觉系统中促进存活、短程神经支配和突触发生的能力存在显著差异。在耳蜗中，特异性通过严格控制的空间和时间配体表达来实现。在前庭系统中，TrkB或TrkC激活足以促进前庭神经节神经元存活，而TrkB激活是促进适当的神经支配和突触发生所必需的。在味觉系统中，NT 3不能替代BDNF的作用，可能是因为TrkB在味觉神经元中的时间选择性表达。我们的结论是，有没有一般的机制，神经营养蛋白特异性的实现和特异性是通过（i）一个严格控制的空间和时间表达的配体，（ii）不同的Trk受体在同一神经元亚群内发挥不同的作用，或（iii）选择性受体表达的感觉神经元亚群。
Neurotrophins have multiple functions during peripheral nervous system development such as controlling neuronal survival, target innervation and synaptogenesis. Neurotrophin specificity has been attributed to the selective expression of the Trk tyrosine kinase receptors in different neuronal subpopulations. However, despite overlapping expression of TrkB and TrkC in many sensory ganglia, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) null mutant mice display selective losses in neuronal subpopulations. In the present study we have replaced the coding part of the BDNF gene in mice with that of NT3 (BDNFNT3/NT3) to analyse the specificity and selective roles of BDNF and NT3 during development. Analysis of BDNFNT3/NT3 mice showed striking differences in the ability of NT3 to promote survival, short-range innervation and synaptogenesis in different sensory systems. In the cochlea, specificity is achieved by a tightly controlled spatial and temporal ligand expression. In the vestibular system TrkB or TrkC activation is sufficient to promote vestibular ganglion neuron survival, while TrkB activation is required to promote proper innervation and synaptogenesis. In the gustatory system, NT3 is unable to replace the actions of BDNF possibly because of a temporally selective expression of TrkB in taste neurons. We conclude that there is no general mechanism by which neurotrophin specificity is attained and that specificity is achieved by (i) a tightly controlled spatial and temporal expression of ligands, (ii) different Trk receptors playing distinct roles within the same neuronal subpopulation, or (iii) selective receptor expression in sensory neuron subpopulations.