Smith M D, Melton L A, Ensor E A, Packham G, Anderson P, Kinloch R A, Latchman D S
Medical Molecular Biology Unit, Institute of Child Health, University College London, United Kingdom.
Mol Cell Neurosci. 2001 Mar;17(3):460-70. doi: 10.1006/mcne.2000.0927.
The determination of cell fate plays a critical role during the later stages of embryogenesis and the early postnatal period-a time during which approximately half of neurons born during neurogenesis undergo programmed cell death. It has previously been reported that the type IV POU domain transcription factor Brn-3a plays a role in the maturation and survival of sensory neuronal populations. Indeed we have shown that the long form of Brn-3a is capable of activating expression of the antiapoptotic Bcl-2 gene and enhancing neuronal survival in cultures of sensory neurons. In this study, we report the identification of another antiapoptotic family member, Bcl-x(L), as a target gene of Brn-3a in sensory neurons, providing a further mechanism by which Brn-3a determines sensory neuronal fate during development. Bcl-x(L) gene expression is activated by Brn-3a in sensory but not in sympathetic neurons and its expression is reduced by antisense inhibition of Brn-3a expression in sensory neurons. Most importantly, both Bcl-x(L) expression and neuronal survival are enhanced by the overexpression of Brn-3a in dorsal root ganglion in vivo in a model of sciatic nerve injury in the intact animal.
细胞命运的决定在胚胎发育后期和出生后早期阶段起着关键作用，在此期间，神经发生过程中产生的神经元约有一半会经历程序性细胞死亡。此前有报道称，IV型POU结构域转录因子Brn-3a在感觉神经元群体的成熟和存活中发挥作用。事实上，我们已经表明，Brn-3a的长形式能够激活抗凋亡Bcl-2基因的表达，并增强感觉神经元培养物中的神经元存活。在本研究中，我们报告了另一种抗凋亡家族成员Bcl-x(L)作为感觉神经元中Brn-3a的靶基因的鉴定，这为Brn-3a在发育过程中决定感觉神经元命运提供了进一步的机制。Bcl-x(L)基因表达在感觉神经元中被Brn-3a激活，但在交感神经元中未被激活，并且在感觉神经元中通过反义抑制Brn-3a表达可降低其表达。最重要的是，在完整动物坐骨神经损伤模型中，通过在背根神经节中过表达Brn-3a，Bcl-x(L)表达和神经元存活均得到增强。
