PGAP1 knock-out mice show otocephaly and male infertility
PGAP1 knock-out mice show otocephaly and male infertility
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DOI：
10.1074/jbc.m705601200
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发表时间：
2007-10-19
影响因子：
4.8
通讯作者：
Kinoshita, Taroh
中科院分区：
文献类型：
--
作者：
Ueda, Yasutaka;Yamaguchi, Ryo;Kinoshita, Taroh
在大多数细胞中，糖基磷脂酰肌醇（GPI）与蛋白质结合后，在内质网中立即去除与肌醇相连的棕榈酸酯。之前，我们发现PGAP1 （GPI后附着于蛋白1）是一种GPI肌醇脱酰酶，可以从肌醇中去除棕榈酸酯。在中国仓鼠卵巢细胞中，尽管GPI-APs在稳定状态下的细胞表面表达正常，但PGAP1的缺陷导致GPI-APs从内质网转运到细胞表面的延迟。然而，在大多数细胞中，gpi - ap经历去酰化。为了阐明PGAP1在体内的生物学意义，我们建立了PGAP1敲除小鼠。大多数PGAP1基因敲除的小鼠表现出耳头畸形，这是一种发育缺陷，出生后立即死亡。然而，有些存活了下来，但生长迟缓。雄性基因敲除小鼠尽管有射精能力，但其生育能力严重下降。他们的精子在数量、活力和上升子宫的能力上都是正常的，但不能进入输卵管。在体外，缺乏pgap1的精子对透明带的附着较弱，受精率严重降低。因此，GPI锚定中额外的酰基链对发育和精子功能造成严重的有害影响。
A palmitate linked to the inositol in glycosylphosphatidylinositol (GPI) is removed in the endoplasmic reticulum immediately after the conjugation of GPI with proteins in most cells. Previously, we identified PGAP1 (post GPI attachment to proteins 1) as a GPI inositoldeacylase that removes the palmitate from inositol. A defect in PGAP1 caused a delay in the transport of GPI-anchored proteins (GPI-APs) from the endoplasmic reticulum to the cell surface in Chinese hamster ovary cells, although the cell-surface expression of GPI-APs in the steady state was normal. Nevertheless, in most cells, GPI-APs undergo deacylation. To elucidate the biological significance of PGAP1 in vivo, we established PGAP1 knock-out mice. Most PGAP1 knock-out mice showed otocephaly, a developmental defect, and died right after birth. However, some survived with growth retardation. Male knock-out mice showed severely reduced fertility despite the capability of ejaculation. Their spermatozoa were normal in number, motility, and ability to ascend the uterus, but were unable to go into the oviduct. In vitro, PGAP1-deficient spermatozoa showed weak attachment to the zona pellucida and a severely diminished rate of fertilization. Therefore, an extra acyl chain in GPI anchors caused severe deleterious effects to development and sperm function.