The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures
The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures
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DOI：
10.1101/gad.855001
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发表时间：
2001-01-15
影响因子：
10.5
通讯作者：
Petkovich, M
中科院分区：
文献类型：
--
作者：
Abu-Abed, S;Dollé, P;Petkovich, M
维生素A的活性衍生物，视黄酸（RA），是正常胚胎发育所必需的。胚胎RA的时空分布是由RA合成的视黄醇脱氢酶和RA代谢的细胞色素P450（CYP 26）的表达调节引起的。过量的RA管理或RA缺乏的结果在一个复杂的频谱胚胎异常。作为理解RA代谢酶的发育功能的第一步，我们已经破坏了小鼠Cyp 26 A1基因。我们报告说，Cyg 26 A1无效突变体在妊娠中后期死亡，并表现出一些主要的形态发生缺陷。脊柱裂和尾部及腰骶部截短（包括肾脏、泌尿生殖道和后肠的异常）是最明显的缺陷，在极端情况下导致sirenomelia（“美人鱼尾”）表型。Cyp 26 A1突变体还显示颈椎的后部转化和头侧后脑的异常图案，这似乎是部分后部转化。这些缺陷与嘴侧神经板和胚胎尾芽中Cyp 26 A1表达的两个主要位点相关。由于所有Cyp 26 A1（-/-）异常与RA致畸作用非常相似，我们推测CYP 26 A1的关键功能是维持特定胚胎区域处于RA耗竭状态，以保护它们免受异位RA信号的有害影响。
The active derivative of vitamin A, retinoic acid (RA), is essential for normal embryonic development. The spatio-temporal distribution of embryonic RA results from regulated expression of RA-synthesizing retinaldehyde dehydrogenases and RA-metabolizing cytochrome P450s (CYP26). Excess RA administration or RA deficiency results in a complex spectrum of embryonic abnormalities. As a first step in understanding the developmental function of RA-metabolizing enzymes, we have disrupted the murine Cyp26A1 gene. We report that Cyg26A1-null mutants die during mid-late gestation and show a number of major morphogenetic defects. Spins bifida and truncation of the tail and lumbosacral region (including abnormalities of the kidneys, urogenital tract, and hindgut) are the most conspicuous defects, leading in extreme cases to a sirenomelia ("mermaid tail") phenotype. Cyp26A1 mutants also show posterior transformations of cervical vertebrae and abnormal patterning of the rostral hindbrain, which appears to be partially posteriorly transformed. These defects correlate with two major sites of Cyp26A1 expression in the rostral neural plate and embryonic tail bud. Because all of the Cyp26A1(-/-) abnormalities closely resemble RA teratogenic effects, we postulate that the key function of CYP26A1 is to maintain specific embryonic areas in a RA-depleted state, to protect them against the deleterious effect of ectopic RA signaling.