García-Díaz Beatriz, Riquelme Raquel, Varela-Nieto Isabel, Jiménez Antonio Jesús, de Diego Isabel, Gómez-Conde Ana Isabel, Matas-Rico Elisa, Aguirre José Ángel, Chun Jerold, Pedraza Carmen, Santín Luis Javier, Fernández Oscar, Rodríguez de Fonseca Fernando, Estivill-Torrús Guillermo
Laboratorio de Investigación, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Hospital Civil, Pabellón 5, Planta Sótano, Plaza del Hospital Civil s/n, 29009, Málaga, Spain.
Department of Neurology, H. Houston Merritt Clinical Research Center, Columbia University Medical Center, New York, NY, 10032, USA.
Brain Struct Funct. 2015 Nov;220(6):3701-20. doi: 10.1007/s00429-014-0885-7. Epub 2014 Sep 17.
Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.
溶血磷脂酸（LPA）是一种细胞间信号脂质，通过特定的G蛋白偶联受体（LPA(1-6)）发挥作用，调节多种细胞功能。我们之前使用存活的马拉加变异型maLPA1基因敲除小鼠进行的研究表明，LPA1受体对于神经前体细胞的正常增殖、分化和存活是必需的。在大脑皮层中，LPA1在分化中的少突胶质细胞中广泛表达，与髓鞘形成同时发生。尽管已经在髓鞘形成细胞中研究了外源性LPA诱导的效应，但LPA1在体内对正常髓鞘形成的作用仍有待证实。本研究确定了LPA1作为皮层髓鞘形成调节因子在体内的相关作用。对成年maLPA1基因敲除小鼠的免疫化学分析表明，大脑皮层中髓鞘蛋白MBP、PLP/DM20和CNPase的稳态水平降低。使用磁共振波谱和电子显微镜证实了髓鞘缺陷。体视学分析将缺陷限制在成年分化中的少突胶质细胞，而NG2+前体细胞没有变化。最后，通过PLP/DM20髓鞘蛋白的细胞内运输受损并伴有细胞丢失，证明了一种可能涉及少突胶质细胞存活的机制，提示应激诱导的细胞凋亡。这些发现描述了LPA1在中枢神经系统少突胶质细胞分化和髓鞘形成调节中以前未被描述的体内功能作用，强调了maLPA1基因敲除小鼠作为脱髓鞘疾病研究模型的重要性。
