Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa1H/+ mouse
Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa1H/+ mouse
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DOI：
10.1016/j.ymgme.2009.06.016
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发表时间：
2009-12-01
影响因子：
3.8
通讯作者：
Herman, Gail E.
中科院分区：
文献类型：
--
作者：
Cunningham, David;Spychala, Kaitlyn;Herman, Gail E.
NSDHL(NAD(P)H类固醇脱氢酶)，是一种3β-羟基固醇脱氢酶，被认为在胆固醇生物合成的后期步骤之一中起到类固醇前体去甲基化的作用。X-连锁NSDHL基因的突变会导致人类的儿童综合征，以及小鼠的男性致死裸露斑块(BPA)表型。用免疫组织化学方法分析NSDHL在小鼠胚胎发育和出生后不同发育阶段不同组织中的相对表达水平。在野生型(WT)胚胎中，肝脏、背根神经节、中枢神经系统、视网膜、肾上腺和睾丸的表达水平最高。由于正常的随机X失活，杂合的BPA(1H)雌性是NSDHL表达的嵌合体。在BPA(1H)雌性胚胎发育中的大脑皮层和视网膜中检测到NSDHL缺陷细胞。在出生后的WT和BPA(1H)动物中，我们比较了NSDHL在皮肤(受影响的组织)、肝脏(胆固醇合成的主要部位)和脑(由于缺乏血脑屏障的运输而依赖内源性胆固醇合成的组织)的表达模式。在BPA(1H)仔鼠的脑、皮肤和肝脏中可见突变细胞的克隆性群体。在肝脏中，NSDHL阴性细胞的比例从出生后6天的50%下降到一岁时的20%。在大脑皮质和海马神经元中表达最高的大脑中，NSDHL阴性细胞的比例在出生后第一年也大幅下降。我们的结果表明，尽管嵌合型BPA(1H)雌性的NSDHL缺陷细胞能够在胚胎发育期间存活和分化，但它们在动物的一生中受到负选择的影响。(C)2009 Elsevier Inc.保留所有权利。
NSDHL (NAD(P)H sterol dehydrogenase-like), is a 3 beta-hydroxysterol dehydrogenase thought to function in the demethylation of sterol precursors in one of the later steps of cholesterol biosynthesis. Mutations in the X-linked NSDHL gene cause CHILD syndrome in humans, and the male-lethal bare patches (Bpa) phenotype in mice. The relative level of NSDHL expression among different mouse tissues at several stages of embryogenesis and postnatal development was analyzed by immunohistochemistry. In wild type (WT) embryos, the highest levels of expression were seen in the liver, dorsal root ganglia, central nervous system, retina, adrenal gland and testis. Heterozygous Bpa(1H) females are mosaic for NSDHL expression due to normal random X-inactivation. NSDHL-deficient cells were detected in the developing cerebral cortex and retina of Bpa(1H) female embryos. In postnatal WT and Bpa(1H) animals, we compared the expression pattern of NSDHL in skin, an affected tissue; liver, a main site of cholesterol synthesis; and brain, a tissue dependent on endogenous synthesis of cholesterol due to lack of transport across the blood-brain barrier. Clonal populations of mutant cells were visible in the brain, skin and liver of Bpa(1H) pups. In the liver, the proportion of NSDHL negative cells dropped from, similar to 50% at postnatal day 6 to similar to 20% at one year of age. In the brain, which showed the highest expression in cerebral cortical and hippocampal neurons, the proportion of NSDHL negative cells also dropped dramatically over the first year of life. Our results suggest that while NSDHL-deficient cells in the mosaic Bpa(1H) female are able to survive and differentiate during embryonic development, they are subject to negative selection over the life of the animal. (C) 2009 Elsevier Inc. All rights reserved.