TAM receptors support neural stem cell survival, proliferation and neuronal differentiation.
TAM receptors support neural stem cell survival, proliferation and neuronal differentiation.
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DOI：
10.1371/journal.pone.0115140
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lu Q
中科院分区：
文献类型：
--
作者：
Ji R;Meng L;Jiang X;Cvm NK;Ding J;Li Q;Lu Q
Tyro 3、Axl和Mertk（TAM）受体酪氨酸激酶通过为细胞生长提供内在营养支持或调节在免疫应答的稳态调节中重要的靶基因的表达而发挥多种功能作用。TAM受体通过负性调节中枢神经系统（CNS）胶质细胞的活化来调节成年海马神经发生。在本研究中，我们进一步证明，所有三个TAM受体表达的培养的原代神经干细胞（NSCs），并发挥了直接的生长营养作用，在NSCs的增殖，神经元分化和生存。培养的缺乏TAM受体的原代神经干细胞表现出生长缓慢，增殖减少和凋亡增加，如通过减少BrdU掺入和增加TUNEL标记所示，比来自WT神经干细胞的那些。此外，突变体NSC的神经元分化和成熟受到阻碍，其特征在于与其WT对应物相比较少的神经元分化（β-微管蛋白III+）和神经突生长。为了阐明TAM受体在分化的NSC中发挥作用的潜在机制，我们通过实时定量PCR检测了来自海马和原代NSC的总RNA上的神经营养因子及其受体的表达谱;并发现TKO NSC显示出神经生长因子（NGF）和脑源性神经营养因子（BDNF）的表达显著降低，但伴随着TrkA、TrkB、TrkC和p75受体表达的代偿性增加。这些结果表明，TAM受体通过调节神经营养因子的表达，特别是神经生长因子的表达，支持神经干细胞的存活，增殖和分化。
Tyro3, Axl and Mertk (TAM) receptor tyrosine kinases play multiple functional roles by either providing intrinsic trophic support for cell growth or regulating the expression of target genes that are important in the homeostatic regulation of immune responses. TAM receptors have been shown to regulate adult hippocampal neurogenesis by negatively regulation of glial cell activation in central nervous system (CNS). In the present study, we further demonstrated that all three TAM receptors were expressed by cultured primary neural stem cells (NSCs) and played a direct growth trophic role in NSCs proliferation, neuronal differentiation and survival. The cultured primary NSCs lacking TAM receptors exhibited slower growth, reduced proliferation and increased apoptosis as shown by decreased BrdU incorporation and increased TUNEL labeling, than those from the WT NSCs. In addition, the neuronal differentiation and maturation of the mutant NSCs were impeded, as characterized by less neuronal differentiation (β-tubulin III+) and neurite outgrowth than their WT counterparts. To elucidate the underlying mechanism that the TAM receptors play on the differentiating NSCs, we examined the expression profile of neurotrophins and their receptors by real-time qPCR on the total RNAs from hippocampus and primary NSCs; and found that the TKO NSC showed a significant reduction in the expression of both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but accompanied by compensational increases in the expression of the TrkA, TrkB, TrkC and p75 receptors. These results suggest that TAM receptors support NSCs survival, proliferation and differentiation by regulating expression of neurotrophins, especially the NGF.
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影响因子：
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Eriksson, PS;Perfilieva, E;Gage, FH
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通讯作者：
Benzakour, Omar