Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse
Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse
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DOI：
10.1111/j.1365-2443.2008.01194.x
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发表时间：
2008-06-01
期刊：
影响因子：
2.1
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Shirane, Michiko;Ogawa, Masaharu;Nakayama, Keiichi I.
FKBP38（也称为FKBP8）是一种跨膜伴侣蛋白，通过向线粒体募集抗凋亡蛋白Bcl-2和Bcl-x(L)来抑制细胞凋亡。我们现在已经培育出了携带Fkbp38功能缺失突变的小鼠。Fkbp38（-/-）小鼠出生后很快死亡，表现为胸腰椎骶区神经管闭合缺陷（脊柱裂）以及脊柱侧凸、肋骨畸形、内翻足和卷曲尾巴等骨骼缺陷。Fkbp38（-/-）胚胎的神经上皮组织紊乱，背根神经节的形成有缺陷，这可能是由于神经元细胞凋亡频率增加和异常迁移的结果。此外，脊髓神经纤维的延伸在突变胚胎中是异常的。为了探索这些特征背后的机制，我们筛选了酵母双杂交系统中与FKBP38相互作用的蛋白质，从而确定了突起蛋白，一种通过调节膜运输促进过程形成的蛋白质。研究发现，在Fkbp38（-/-）小鼠的大脑中，突起蛋白被过度磷酸化，这表明Fkbp38调节突起蛋白依赖的膜循环和神经突的生长。总之，我们的研究结果表明，在神经管形成过程中，FKBP38是神经外胚层组织所必需的，因为它具有抗凋亡活性和调节神经突延伸。
FKBP38 (also known as FKBP8) is a transmembrane chaperone protein that inhibits apoptosis by recruiting the anti-apoptotic proteins Bcl-2 and Bcl-x(L) to mitochondria. We have now generated mice harboring a loss-of-function mutation in Fkbp38. The Fkbp38(-/-) mice die soon after birth manifesting defects in neural tube closure in the thoraco-lumbar-sacral region (spina bifida) as well as skeletal defects including scoliosis, rib deformities, club foot and curled tail. The neuroepithelium is disorganized and that formation of dorsal root ganglia is defective in Fkbp38(-/-) embryos, likely as a result of an increased frequency of apoptosis and aberrant migration of neuronal cells. Furthermore, the extension of nerve fibers in the spinal cord is abnormal in the mutant embryos. To explore the mechanisms underlying these characteristics, we screened for proteins that interact with FKBP38 in the yeast two-hybrid system and thereby identified protrudin, a protein that promotes process formation by regulating membrane trafficking. Protrudin was found to be hyperphosphorylated in the brain of Fkbp38(-/-) mice, suggesting that FKBP38 regulates protrudin-dependent membrane recycling and neurite outgrowth. Together, our findings suggest that FKBP38 is required for neuroectodermal organization during neural tube formation as a result of its anti-apoptotic activity and regulation of neurite extension.