A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure.
A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure.
复制标题
DOI：
10.1242/dmm.024109
复制
发表时间：
2016-05-01
影响因子：
4.3
通讯作者：
Lozanoff S
中科院分区：
文献类型：
--
作者：
Fong KS;Hufnagel RB;Khadka VS;Corley MJ;Maunakea AK;Fogelgren B;Ahmed ZM;Lozanoff S
影响沿头部神经管闭合的遗传变异导致面部和大脑畸形。神经管缺陷是人类最常见的先天缺陷之一。我们之前报道了一种叫做tuft的小鼠突变体，它在我们的野生型3H1菌落中自发产生。成年簇状小鼠呈现颅面中线畸形，伴或不伴前头膨出。此外，受影响的胚胎出现神经管闭合缺陷，导致前神经孔闭合不足或畸形。在这里，通过全基因组测序，我们在Tet1基因中发现了一个无义突变，该突变编码甲基胞嘧啶双加氧酶（Tet1），与簇状表型共分离。这种突变导致过早终止，破坏了参与胞嘧啶去甲基化的催化结构域。我们在突变纯合子的簇状胚胎的头部检测到TET酶活性的显著丧失，并且具有NTDs。RNA-Seq转录组分析表明，与神经管闭合相关的多个基因通路在簇状胚头中失调。其中，Cecr2、Epha7和Grhl2的表达在部分出现神经管闭合缺陷的胚胎中显著降低，而介导平面细胞极性和趋同扩展的非规范WNT信号通路的一个或多个组分在其他胚胎中受到影响。我们进一步发现，重组突变TET1蛋白能够进入细胞核，并影响内源性Grhl2在IMCD-3（内髓集管）细胞中的表达。这些结果表明，TET1是调控基因的表观遗传决定因素，这些基因对前神经管的闭合至关重要，其突变对颅面发育有影响，正如簇毛小鼠所展示的那样。摘要：我们提出了一种表观遗传机制，建立了对神经管闭合至关重要的基因调控。这种机制可能是解决这类出生缺陷和相关疾病的新靶点。
Genetic variations affecting neural tube closure along the head result in malformations of the face and brain. Neural tube defects (NTDs) are among the most common birth defects in humans. We previously reported a mouse mutant called tuft that arose spontaneously in our wild-type 3H1 colony. Adult tuft mice present midline craniofacial malformations with or without an anterior cephalocele. In addition, affected embryos presented neural tube closure defects resulting in insufficient closure of the anterior neuropore or exencephaly. Here, through whole-genome sequencing, we identified a nonsense mutation in the Tet1 gene, which encodes a methylcytosine dioxygenase (TET1), co-segregating with the tuft phenotype. This mutation resulted in premature termination that disrupts the catalytic domain that is involved in the demethylation of cytosine. We detected a significant loss of TET enzyme activity in the heads of tuft embryos that were homozygous for the mutation and had NTDs. RNA-Seq transcriptome analysis indicated that multiple gene pathways associated with neural tube closure were dysregulated in tuft embryo heads. Among them, the expressions of Cecr2, Epha7 and Grhl2 were significantly reduced in some embryos presenting neural tube closure defects, whereas one or more components of the non-canonical WNT signaling pathway mediating planar cell polarity and convergent extension were affected in others. We further show that the recombinant mutant TET1 protein was capable of entering the nucleus and affected the expression of endogenous Grhl2 in IMCD-3 (inner medullary collecting duct) cells. These results indicate that TET1 is an epigenetic determinant for regulating genes that are crucial to closure of the anterior neural tube and its mutation has implications to craniofacial development, as presented by the tuft mouse. Summary: We propose an epigenetic mechanism establishing the regulation of genes that are crucial for neural tube closure. This mechanism could be a novel target for resolving such birth defects and associated disorders.