MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome.
MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome.
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DOI：
10.1038/s41598-021-83771-3
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发表时间：
2021-03-02
影响因子：
4.6
通讯作者：
Van Esch H
中科院分区：
文献类型：
--
作者：
Thues C;Valadas JS;Deaulmerie L;Geens A;Chouhan AK;Duran-Romaña R;Schymkowitz J;Rousseau F;Bartusel M;Rehimi R;Rada-Iglesias A;Verstreken P;Van Esch H
圆周皮肤皱纹（CSC-KT）是一种罕见的多畸形综合征，其特征是与四肢皮肤皱纹相关的智力障碍和非常典型的颅面畸形。此前，MAPRE2 杂合和纯合突变被发现是导致这种疾病的原因。 MAPRE2 编码进化保守微管加末端追踪蛋白的成员，即末端结合 (EB) 家族。与 MAPRE1 和 MAPRE3 不同，MAPRE2 不是微管持续生长和稳定所必需的，但在其他细胞过程中发挥作用，例如有丝分裂进展和细胞粘附调节。 MAPRE2 中发现的突变均位于钙调蛋白同源结构域内，负责跟踪生长微管的正端并与之相互作用，之前的数据表明，改变 MAPRE2 剂量会导致斑马鱼鳃弓模式异常。在这项研究中，我们使用 CRISPR/Cas9 技术开发了源自患者的 MAPRE2 诱导多能干细胞系以及同基因对照，并将它们分化为具有颅特征的神经嵴细胞。我们发现，将神经嵴祖细胞异种移植到发育中的鸡胚胎后，MAPRE2 的变化会导致体外和体内神经嵴迁移的改变。此外，我们提供的证据表明，粘着斑的变化可能是 MAPRE2 突变型颅神经嵴细胞细胞运动改变的基础。我们的数据提供了证据表明 MAPRE2 参与颅神经嵴的细胞迁移，并为 CSC-KT 患者中存在的颅面畸形和腭裂的潜在机制提供了重要的见解。这将 CSC-KT 疾病添加到了不断增长的神经脆病列表中。
Circumferential skin creases (CSC-KT) is a rare polymalformative syndrome characterised by intellectual disability associated with skin creases on the limbs, and very characteristic craniofacial malformations. Previously, heterozygous and homozygous mutations in MAPRE2 were found to be causal for this disease. MAPRE2 encodes for a member of evolutionary conserved microtubule plus end tracking proteins, the end binding (EB) family. Unlike MAPRE1 and MAPRE3, MAPRE2 is not required for the persistent growth and stabilization of microtubules, but plays a role in other cellular processes such as mitotic progression and regulation of cell adhesion. The mutations identified in MAPRE2 all reside within the calponin homology domain, responsible to track and interact with the plus-end tip of growing microtubules, and previous data showed that altered dosage of MAPRE2 resulted in abnormal branchial arch patterning in zebrafish. In this study, we developed patient derived induced pluripotent stem cell lines for MAPRE2, together with isogenic controls, using CRISPR/Cas9 technology, and differentiated them towards neural crest cells with cranial identity. We show that changes in MAPRE2 lead to alterations in neural crest migration in vitro but also in vivo, following xenotransplantation of neural crest progenitors into developing chicken embryos. In addition, we provide evidence that changes in focal adhesion might underlie the altered cell motility of the MAPRE2 mutant cranial neural crest cells. Our data provide evidence that MAPRE2 is involved in cellular migration of cranial neural crest and offers critical insights into the mechanism underlying the craniofacial dysmorphisms and cleft palate present in CSC-KT patients. This adds the CSC-KT disorder to the growing list of neurocristopathies.
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一个 iCRISPR 平台，用于在人类多能干细胞中进行快速、可多重、可诱导的基因组编辑。
影响因子：
23.9
作者：
Gonzalez, Federico;Zhu, Zengrong;Shi, Zhong-Dong;Lelli, Katherine;Verma, Nipun;Li, Qing V.;Huangfu, Danwei
通讯作者：
Huangfu, Danwei
影响因子：
4.3
作者：
Castillo V;Ventura S
通讯作者：
Ventura S
影响因子：
23.9
作者：
Laugsch, Magdalena;Bartusel, Michaela;Rada-Iglesias, Alvaro
通讯作者：
Rada-Iglesias, Alvaro
影响因子：
9.8
作者：
Isrie, Mala;Breuss, Martin;Van Esch, Hilde
通讯作者：
Van Esch, Hilde
影响因子：
3
作者：
Conchillo-Solé O;de Groot NS;Avilés FX;Vendrell J;Daura X;Ventura S
通讯作者：
Ventura S