Herrera Victoria L M, Decano Julius L, Bagamasbad Pia, Kufahl Timothy, Steffen Martin, Ruiz-Opazo Nelson
Department of Medicine, Section of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Physiol Genomics. 2008 Nov 12;35(3):316-29. doi: 10.1152/physiolgenomics.00044.2008. Epub 2008 Sep 9.
Aside from abnormal angiogenesis, dual endothelin-1/VEGF signal peptide-activated receptor deficiency (DEspR(-/-)) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role in neurogenesis. With the emerging importance of neurogenesis in adulthood, we tested the hypothesis that nonembryonic-lethal DEspR haploinsufficiency (DEspR(+/-)) perturbs neuronal homeostasis, thereby facilitating aging-associated neurodegeneration. Here we show that, in male mice only, DEspR-haploinsufficiency impaired hippocampus-dependent visuospatial and associative learning and induced noninflammatory spongiform changes, neuronal vacuolation, and loss in the hippocampus, cerebral cortex, and subcortical regions, consistent with autophagic cell death. In contrast, DEspR(+/-) females exhibited better cognitive performance than wild-type females and showed absence of neuropathological changes. Signaling pathway analysis revealed DEspR-mediated phosphorylation of activators of autophagy inhibitor mammalian target of rapamycin (mTOR) and dephosphorylation of known autophagy inducers. Altogether, the data demonstrate DEspR-mediated diametrical, sex-specific modulation of cognitive performance and autophagy, highlight cerebral neuronal vulnerability to autophagic dysregulation, and causally link DEspR haploinsufficiency with increased neuronal autophagy, spongiosis, and cognitive decline in mice.
除了异常血管生成外，内皮素-1/血管内皮生长因子双信号肽激活受体缺陷（DEspR(-/-)）会导致神经上皮和神经管分化异常，从而阐明了DEspR在神经发生中的作用。随着成年期神经发生的重要性日益凸显，我们检验了以下假设：非胚胎致死性的DEspR单倍体不足（DEspR(+/-)）会扰乱神经元稳态，从而促进与衰老相关的神经退行性变。在此我们表明，仅在雄性小鼠中，DEspR单倍体不足会损害依赖海马体的视觉空间和联想学习能力，并在海马体、大脑皮层和皮层下区域诱导非炎性海绵状变化、神经元空泡化和神经元丢失，这与自噬性细胞死亡一致。相比之下，DEspR(+/-)雌性小鼠的认知表现优于野生型雌性小鼠，且未出现神经病理学变化。信号通路分析显示，DEspR介导自噬抑制剂哺乳动物雷帕霉素靶蛋白（mTOR）激活剂的磷酸化以及已知自噬诱导剂的去磷酸化。总之，这些数据证明了DEspR介导的认知表现和自噬的双向、性别特异性调节，突出了大脑神经元对自噬失调的易感性，并将DEspR单倍体不足与小鼠神经元自噬增加、海绵样变和认知衰退因果联系起来。
