The analysis of PDGFR-β deficient brain

血小板衍生生长因子（PDGF）和PDGF受体（pdgfr）在哺乳动物中枢神经系统中广泛表达，但其功能意义尚不清楚。为了阐明PDGFR在中枢神经系统中的功能，我们开发了一种新的突变小鼠，其中编码PDGFR b亚基的基因（PDGFR-b）在中枢神经系统神经元中被基因删除，以阐明PDGFR-b的作用，特别是在出生后阶段，并分析了突变小鼠。1)与对照组相比，突变体低温损伤后的脑损伤严重加重。此外，直接注射NMDA后，tdt介导的dutp -生物素缺口末端标记（TUNEL）阳性的大脑半球神经元细胞死亡和病变形成在我们的突变小鼠中广泛加剧，而NMDA受体的表达没有改变。我们的研究结果清楚地表明，PDGFR-b在神经元中的表达保护它们免受低温损伤和nmda诱导的兴奋性毒性。2)采用片膜片钳技术，研究了PDGF-BB对孤束核（NTS） AMPA功能的抑制作用。PDGF-BB可显著降低NTS神经元AMPA诱导电流的振幅，表明PDGF-BB可通过突触后机制抑制AMPA受体介导的兴奋性输入。PDGF-BB对神经元中PDGFR-β基因条件缺失的突变小鼠EPSCs的抑制作用未被观察到。这些研究表明PDGF-B/PDGFR-β轴抑制AMPA受体介导的突触传递，该突触传递是NTS二级神经元初级传入的主要部分。检测到的抑制作用可能与中枢神经系统对呼吸反应的调节有关。3) PDGFRB-/-神经干细胞凋亡率升高，但增殖未见明显下降。它们在PDGF-BB和bFGF的作用下表现出迁移和神经元分化能力的降低。bFGF增加了PDGFRB启动子的活性以及PDGFRB的表达和磷酸化。这些结果表明PDGF和FGF之间存在信号趋同。PDGFRB是生存所必需的，而bFGF在细胞迁移和神经分化中的作用可能通过诱导PDGFRB而增强。少

Platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) are widely expressed in the mammalian CNS, though their functional significance remains unclear. To clarify PDGFR function in CNS, we developed novel mutant mice in which the gene encoding the b subunit of PDGFR (PDGFR-b) was genetically deleted in CNS neurons to elucidate the role of PDGFR-b, particularly in the post-natal stage and analyzed the mutant mice.1) The cerebral damage after cryogenic injury was severely exacerbated in the mutants compared with controls. Furthermore, TdT-mediated dUTP-biotin nick end labeling (TUNEL)- positive neuronal cell death and lesion formation in the cerebral hemisphere were extensively exacerbated in our mutant mice after direct injection of NMDA without altered NMDA receptor expression. Our results clearly demonstrate that PDGFR-b expressed in neurons protects them from cryogenic injury and NMDA-induced excitotoxicity.2) We examined the inhibitory effect of PDGF-BB on the AMPA rece … More ptor function in the nucleus tractus solitarius (NTS) by using slice patch-clamp techniques. PDGF-BB significantly reduced the amplitude of AMPA-induced currents in NTS neurons, which showed that PDGF-BB could suppress the AMPA receptor-mediated excitatory input via the postsynaptic mechanism. The inhibitory effect of PDGF-BB on EPSCs was not observed in mutant mice with conditional deletion of the PDGFR-β gene in neurons. These studies suggest that the PDGF-B/PDGFR-β axis inhibits the AMPA receptormediated synaptic transmission that comprises the major part of the primary afferent to the NTS second-order neuron. The detected inhibitory action may be involved in the CNS regulation of the respiratory response.3) PDGFRB-/-neural stem cells showed a higher rate of apoptosis without any significant decrease in proliferation. They demonstrated reduced capacities of migration and neuronal differentiation in response to not only PDGF-BB but also bFGF. bFGF increased the activity of the PDGFRB promoter as well as the expression and phosphorylation of PDGFRB. These results suggest the presence of the signaling convergence between PDGF and FGF. PDGFRB is needed for survival, and the effects of bFGF in migration and neural differentiation of the cells may be potentiated by induction of PDGFRB. Less