Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia.
Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia.
复制标题
在家族性自主神经异常模型中，Elp1的缺失会破坏三叉神经节神经发育。
DOI：
10.7554/elife.71455
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发表时间：
2022-06-17
期刊：
影响因子：
7.7
通讯作者：
Taneyhill, Lisa A.
中科院分区：
文献类型：
--
作者：
Leonard, Carrie E.;Quiros, Jolie;Lefcort, Frances;Taneyhill, Lisa A.
关键词：
家族性自主神经功能障碍(FD)是由延伸器复合体蛋白1(ELP1)基因突变引起的感觉和自主神经病变。FD患者三叉神经较小，面部疼痛和温觉受损。这些信号由三叉神经节中的伤害性神经元传递，三叉神经节是一个由神经脊和胎盘来源的细胞组成的结构。缺乏Elp1神经峰衍生物(Elp1 CKO)的小鼠出生时就有三叉神经节，这表明Elp1对三叉神经节的发育很重要，但Elp1在这方面的功能尚不清楚。我们证明，Elp1在神经脊和胎盘来源的神经元中都表达，在三叉神经节的初始形成中不是必需的。然而，Elp1CKO三叉神经元轴突长出异常，靶神经支配不足。发育中的表达TrkA受体的伤害性感受器在Elp1CKO发生早期凋亡，而表达TrkB和TrkC的神经元则幸免于难，这表明Elp1支持三叉神经伤害性感受器的靶神经支配和生存。此外，我们证明Elp1CKO三叉神经节中的特异性TrkA缺陷反映了大多数TrkA神经元的神经脊谱系，而不是大多数TrkB和TrkC神经元的胎盘谱系。总之，这些发现解释了可能导致FD患者面部疼痛和温觉丧失的颅神经节形成缺陷。
Familial dysautonomia (FD) is a sensory and autonomic neuropathy caused by mutations in elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired facial pain and temperature perception. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure that is composed of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives (‘Elp1 CKO’) are born with small trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate that Elp1, expressed in both neural crest- and placode-derived neurons, is not required for initial trigeminal ganglion formation. However, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and deficient target innervation. Developing nociceptors expressing the receptor TrkA undergo early apoptosis in Elp1 CKO, while TrkB- and TrkC-expressing neurons are spared, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. Furthermore, we demonstrate that specific TrkA deficits in the Elp1 CKO trigeminal ganglion reflect the neural crest lineage of most TrkA neurons versus the placodal lineage of most TrkB and TrkC neurons. Altogether, these findings explain defects in cranial gangliogenesis that may lead to loss of facial pain and temperature sensation in FD.
影响因子：
5.4
作者：
Yajima H;Suzuki M;Ochi H;Ikeda K;Sato S;Yamamura K;Ogino H;Ueno N;Kawakami K
通讯作者：
Kawakami K