Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons
Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons
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DOI：
10.1073/pnas.1308596110
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发表时间：
2013-11-12
影响因子：
11.1
通讯作者：
Lefcort, Frances
中科院分区：
文献类型：
--
作者：
George, Lynn;Chaverra, Marta;Lefcort, Frances
家族性自主神经功能障碍（FD）是由κ B激酶复合物相关蛋白（IKBKAP）基因抑制剂突变引起的一种破坏性的发育和进行性周围神经病变。为了鉴定引起FD的细胞和分子机制，我们产生了外周神经系统中Ikbkap表达被消融的小鼠，并鉴定了外周神经系统发育中依赖Ikbkap的步骤。我们发现，Ikbkap是不需要的躯干神经嵴迁移或寻路，也不是背根或交感神经节，或肾上腺髓质的形成。相反，Ikbkap对于神经发生的第二波是必需的，在此期间，大多数原肌球蛋白相关激酶A（TrkA（+））伤害感受器和温度感受器出现。在其缺失的情况下，大约一半的TrkA（+）神经元的正常补体丢失，我们表明这部分是由于p53介导的过早分化和有丝分裂活性祖细胞的死亡，这些祖细胞表达配对盒基因Pax3并产生大多数TrkA（+）神经元。到感觉发育结束时，TrkC神经元的数量显著增加，这可能是Runx3（+）细胞增加的结果。此外，我们的数据表明，TrkA（+）（而不是TrkC（+））的感觉和交感神经元经历加剧的Caspase 3介导的程序性细胞死亡在Ikbkap的情况下，这种死亡不是由于神经生长因子合成的减少。总之，这些数据表明，FD不是由躯干神经嵴迁移失败引起的，而是由TrkA祖细胞和TrkA（+）神经元中Ikbkap的关键功能引起的。
Familial dysautonomia (FD) is a devastating developmental and progressive peripheral neuropathy caused by a mutation in the gene inhibitor of kappa B kinase complex-associated protein (IKBKAP). To identify the cellular and molecular mechanisms that cause FD, we generated mice in which Ikbkap expression is ablated in the peripheral nervous system and identify the steps in peripheral nervous system development that are Ikbkap-dependent. We show that Ikbkap is not required for trunk neural crest migration or pathfinding, nor for the formation of dorsal root or sympathetic ganglia, or the adrenal medulla. Instead, Ikbkap is essential for the second wave of neurogenesis during which the majority of tropomyosin-related kinase A (TrkA(+)) nociceptors and thermoreceptors arise. In its absence, approximately half the normal complement of TrkA(+) neurons are lost, which we show is partly due to p53-mediated premature differentiation and death of mitotically-active progenitors that express the paired-box gene Pax3 and give rise to the majority of TrkA(+) neurons. By the end of sensory development, the number of TrkC neurons is significantly increased, which may result from an increase in Runx3(+) cells. Furthermore, our data demonstrate that TrkA(+) (but not TrkC(+)) sensory and sympathetic neurons undergo exacerbated Caspase 3-mediated programmed cell death in the absence of Ikbkap and that this death is not due to a reduction in nerve growth factor synthesis. In summary, these data suggest that FD does not result from a failure in trunk neural crest migration, but rather from a critical function for Ikbkap in TrkA progenitors and TrkA(+) neurons.