The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system.
The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system.
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DOI：
10.1242/dmm.028258
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发表时间：
2017-05-01
影响因子：
4.3
通讯作者：
Lefcort F
中科院分区：
文献类型：
--
作者：
Chaverra M;George L;Mergy M;Waller H;Kujawa K;Murnion C;Sharples E;Thorne J;Podgajny N;Grindeland A;Ueki Y;Eiger S;Cusick C;Babcock AM;Carlson GA;Lefcort F
遗传性感觉和自主神经病（HSAN）是一组遗传和临床多样性的疾病，定义为周围神经系统（PNS）功能障碍。HSAN III型，被称为家族性自主神经功能障碍（FD），是由基因IKBKAP中的单碱基突变引起的，该基因编码一个多亚基复合物（称为Elongator）的支架单元（ELP1）。由于其他延长子亚基（ELP2至ELP4）的突变与中枢神经系统（CNS）疾病相关，因此本研究的目的是研究小鼠CNS中对Ikbkap的潜在需求。FD的感觉和自主神经病理生理学是致命的，大多数患者在40岁之前死亡。虽然在CNS中已经注意到FD的体征和病理学，但临床和研究的重点一直是感觉和自主神经功能障碍，并且没有遗传模型研究调查CNS中对Ikbkap的需求。在这里，我们报告，使用一种新的小鼠线，其中Ikbkap是删除仅在神经系统中，不仅是Ikbkap广泛表达在胚胎和成人中枢神经系统，但它的删除干扰皮质神经元的发育和他们的生存在成年期。胚胎皮层顶端祖细胞的初级纤毛和成体室管膜细胞的运动纤毛数量减少且排列紊乱。此外，我们报告说，在成人中枢神经系统，自主和非自主神经元群体需要Ikbkap生存，包括脊髓运动和皮质神经元。此外，小鼠出现脊柱后凸，这是FD的标志，表明其神经病理性病因。最终，这些扰动表现为发育和进行性神经退行性疾病，包括学习和记忆障碍。总的来说，这些数据揭示了Ikbkap的基本功能，其延伸到外周神经系统以外的CNS发育和功能。随着依赖于Ikbkap的离散CNS细胞类型和结构的鉴定，可以开发新的策略来阻止FD中CNS神经元的进行性死亡。总结：Ikbkap对正常CNS发育、神经元存活和行为是必不可少的，增加了我们对哺乳动物CNS中延长子复合物的作用的理解。
Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed. Summary: Ikbkap is essential for normal CNS development, neuronal survival and behavior, adding to our understanding of the role of the Elongator complex in the mammalian CNS.