De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome
De novo inbred heterozygous Zeb2/Sip1 mutant mice uniquely generated by germ-line conditional knockout exhibit craniofacial, callosal and behavioral defects associated with Mowat-Wilson syndrome
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DOI：
10.1093/hmg/ddv350
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发表时间：
2015-11-15
影响因子：
3.5
通讯作者：
Higashi, Yujiro
中科院分区：
文献类型：
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作者：
Takagi, Tsuyoshi;Nishizaki, Yuriko;Higashi, Yujiro
Mowat-Wilson综合征（MOWS）是由ZEB2（SIP1、ZFHX1B）基因的新杂合突变引起的，表现出中度至重度智力障碍（ID）、特征性面部外观、癫痫和其他先天性异常。建立小鼠 MOWS 模型很重要，不仅对于研究这种疾病的发病机制，而且对于鉴定可能改善症状的化合物也很重要。然而，由于杂合子Zeb2敲除小鼠无法维持为具有近交C57BL/6背景的小鼠系，因此很难将这些小鼠用于MOWS的研究。在这里，我们通过使用条件重组系统在生殖细胞中诱导 Zeb2 突变，系统地从头生成了 Zeb2 Delta ex7/+ 小鼠。具有 C57BL/6 背景的从头 Zeb2 Delta ex7/+ 小鼠出现了与 MOWS 相关的多种缺陷，包括颅面异常、胼胝体形成缺陷和皮质中小清蛋白中间神经元数量减少。在行为分析中，这些小鼠表现出运动活动减少、焦虑增加和社交能力受损。值得注意的是，在巴恩斯迷宫测试中，在重复试验中观察到不动的 Zeb2 突变小鼠。相比之下，具有封闭集落 ICR 背景的小鼠品系和新生 Zeb2 Delta ex7/+ 小鼠均未表现出颅骨异常或运动活动减少。这些结果证明了使用具有 C57BL/6 背景的 de novo Zeb2 Delta ex7/+ 小鼠作为 MOWS 模型的优势。据我们所知，这是首次将诱导性从头突变系统应用于小鼠生殖细胞以产生人类先天性疾病的动物模型。
Mowat-Wilson syndrome (MOWS) is caused by de novo heterozygous mutation at ZEB2 (SIP1, ZFHX1B) gene, and exhibit moderate to severe intellectual disability (ID), a characteristic facial appearance, epilepsy and other congenital anomalies. Establishing a murine MOWS model is important, not only for investigating the pathogenesis of this disease, but also for identifying compounds that may improve the symptoms. However, because the heterozygous Zeb2 knockout mouse could not be maintained as a mouse line with the inbred C57BL/6 background, it was difficult to use those mice for the study of MOWS. Here, we systematically generated de novo Zeb2 Delta ex7/+ mice by inducing the Zeb2 mutation in the germ cells using conditional recombination system. The de novo Zeb2 Delta ex7/+ mice with C57BL/6 background developed multiple defects relevant to MOWS, including craniofacial abnormalities, defective corpus callosum formation and the decreased number of parvalbumin interneurons in the cortex. In behavioral analyses, these mice showed reduced motor activity, increased anxiety and impaired sociability. Notably, during the Barnes maze test, immobile Zeb2 mutant mice were observed over repeated trials. In contrast, neither the mouse line nor the de novo Zeb2 Delta ex7/+ mice with the closed colony ICR background showed cranial abnormalities or reduced motor activities. These results demonstrate the advantages of using de novo Zeb2 Delta ex7/+ mice with the C57BL/6 background as the MOWS model. To our knowledge, this is the first time an inducible de novo mutation system has been applied to murine germline cells to produce an animal model of a human congenital disease.