Disrupted blastocoele formation reveals a critical developmental role for long-chain acyl-CoA dehydrogenase
Disrupted blastocoele formation reveals a critical developmental role for long-chain acyl-CoA dehydrogenase
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DOI：
10.1016/j.ymgme.2004.06.001
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发表时间：
2004-08-01
影响因子：
3.8
通讯作者：
Wood, PA
中科院分区：
文献类型：
--
作者：
Berger, PS;Wood, PA
在人类患者中尚未发现长链酰基辅酶A脱氢酶（LCAD）缺乏症。已经存在通过基因靶向策略开发的LCAD缺陷（LCAD-/-）小鼠模型，其具有妊娠丢失作为其表型的一部分。我们测试了LCAD缺乏破坏正常胚胎发育的假设，并至少部分解释了小鼠的妊娠丢失，并可能提出一种机制来解释缺乏这种遗传性酶缺乏症的任何人类患者。我们培养并评估了三种不同基因型的胚胎：LCAD+/+，LCAD+/-和LCAD-/-。我们发现在桑椹胚-囊胚转化时，LCAD-/-胚胎的死亡率显著增加（P < 0.012），表明完成囊胚腔发育和囊胚形成的能力不足。此外，我们假设，我们可以拯救LCAD-/-胚胎在文化中提供多余的脂肪酸的链长，可以很容易地被他们氧化，尽管他们的遗传性酶缺乏。然而，我们无法通过向培养基中补充各种链长的脂肪酸来证明任何拯救。因此，总体而言，我们证明了LCAD-/-胚胎发育超过桑椹胚阶段的能力严重不足，与LCAD+/+胚胎相比，在LCAD+/-胚胎中发现了中等的发育速率。此外，我们无法用任何脂肪酸补充剂挽救LCAD-/-胚胎。(C)2004年爱思唯尔公司长链酰基辅酶A脱氢酶（LCAD）缺乏症尚未在人类患者中发现。已经存在通过基因靶向策略开发的LCAD缺陷（LCAD-/-）小鼠模型，其具有妊娠丢失作为其表型的一部分。我们测试了LCAD缺乏破坏正常胚胎发育的假设，并至少部分解释了小鼠的妊娠丢失，并可能提出一种机制来解释缺乏这种遗传性酶缺乏症的任何人类患者。我们培养并评估了三种不同基因型的胚胎：LCAD+/+，LCAD+/-和LCAD-/-。我们发现在桑椹胚-囊胚转换时，LCAD-/-胚胎的死亡率显著增加（P <0.012），表明完成囊胚腔发育和囊胚形成的能力不足。此外，我们假设，我们可以拯救LCAD-/-胚胎在文化中提供多余的脂肪酸的链长，可以很容易地被他们氧化，尽管他们的遗传性酶缺乏。然而，我们无法通过向培养基中补充各种链长的脂肪酸来证明任何拯救。因此，总体而言，我们证明了LCAD-/-胚胎发育超过桑椹胚阶段的能力严重不足，与LCAD+/+胚胎相比，在LCAD+/-胚胎中发现了中等的发育速率。此外，我们无法用任何脂肪酸补充剂挽救LCAD-/-胚胎。(c)2004年爱思唯尔公司All rights reserved.
Long-chain acyl-CoA dehydrogenase (LCAD) deficiency has not been found in human patients. There has been an LCAD deficient (LCAD-/-) mouse model developed via gene targeting strategies that has gestational loss as a part of its phenotype. We tested the hypothesis that LCAD deficiency disrupts normal embryonic development and explains at least in part the gestational loss in the mouse and may suggest a mechanism to explain the lack of any human patients with this inherited enzyme deficiency. We cultured and evaluated embryos with three different genotypes: LCAD+/+, LCAD+/-, and LCAD-/-. We found a significantly increased rate of death (P < 0.012) in LCAD-/- embryos at the morula-to-blastocyst conversion indicating a deficient ability to complete the development of a blastocoele and formation of a blastocyst. Furthermore, we hypothesized that we could rescue LCAD-/- embryos in culture by supplying excess fatty acids of chain-lengths that could be readily oxidized by them despite their inherited enzyme deficiency. We were unable, however, to demonstrate any rescue by supplementing the culture medium with fatty acids of a wide-range of chain-lengths. Therefore, overall we demonstrated a severely deficient capacity for LCAD-/- embryos to develop past the morula stage with intermediate rates of development found in the LCAD+/- embryos as compared to the LCAD+/+ embryos. Furthermore, we were unable to rescue the LCAD-/- embryos with any fatty acid supplementation. (C) 2004 Elsevier Inc. All rights reserved.Long-chain acyl-CoA dehydrogenase (LCAD) deficiency has not been found in human patients. There has been an LCAD deficient (LCAD-/-) mouse model developed via gene targeting strategies that has gestational loss as a part of its phenotype. We tested the hypothesis that LCAD deficiency disrupts normal embryonic development and explains at least in part the gestational loss in the mouse and may suggest a mechanism to explain the lack of any human patients with this inherited enzyme deficiency. We cultured and evaluated embryos with three different genotypes: LCAD+/+, LCAD+/-, and LCAD-/-. We found a significantly increased rate of death (P < 0.0 12) in LCAD-/- embryos at the morula-to-blastocyst conversion indicating a deficient ability to complete the development of a blastocoele and formation of a blastocyst. Furthermore, we hypothesized that we could rescue LCAD-/- embryos in culture by supplying excess fatty acids of chain-lengths that could be readily oxidized by them despite their inherited enzyme deficiency. We were unable, however, to demonstrate any rescue by supplementing the culture medium with fatty acids of a wide-range of chain-lengths. Therefore, overall we demonstrated a severely deficient capacity for LCAD-/- embryos to develop past the morula stage with intermediate rates of development found in the LCAD+/- embryos as compared to the LCAD+/+ embryos. Furthermore, we were unable to rescue the LCAD-/- embryos with any fatty acid supplementation. (c) 2004 Elsevier Inc. All rights reserved.