MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development
MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development
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DOI：
10.1530/joe-16-0323
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发表时间：
2017-02-01
影响因子：
4
通讯作者：
Darras, Veerle M.
中科院分区：
文献类型：
--
作者：
Delbaere, Joke;Vancamp, Pieter;Darras, Veerle M.
编码甲状腺激素转运蛋白单羧酸转运蛋白8（MCT 8）的人SLC 16 A2基因的失活突变导致Allan-Herndon-达德利综合征伴重度运动缺陷。以鸡为模型，研究了相关小脑发育不良的潜在机制。将MCT 8-RNAi载体电穿孔到3天大胚胎的小脑中允许在浦肯野细胞前体中敲低MCT 8。这导致第6天甲状腺激素反应基因ROR α和浦肯野细胞特异性分化标志物LHX 1/5的下调。MCT 8敲除还导致第18天的树枝状树更小且不那么复杂，这表明MCT 8在细胞自主性浦肯野细胞成熟中发挥着关键作用。早期给予甲状腺激素类似物3，5，3 '-三碘甲状腺乙酸部分挽救了早期浦肯野细胞分化。MCT 8缺陷型浦肯野细胞也诱导非自主效应，因为它们导致颗粒细胞前体增殖减少、外胚层变薄和PAX 6表达丧失。相比之下，在第18天，外胚层厚度增加，在放射状迁移的初始阶段Axonin-1阳性有丝分裂后颗粒细胞的存在增加。伴随着推定的迁移颗粒细胞在分子层中的积累，表明向内径向迁移到内部颗粒层停滞。总之，在浦肯野细胞中的早期MCT 8缺陷导致对小脑发育的细胞自主和非自主影响，并表明MCT 8表达是从非常早期的发展阶段是必不可少的，提供了一个新的见解Allan-Herndon-达德利综合征的个体发生。
Inactivating mutations in the human SLC16A2 gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in the Allan-Herndon-Dudley syndrome accompanied by severe locomotor deficits. The underlying mechanisms of the associated cerebellar maldevelopment were studied using the chicken as a model. Electroporation of an MCT8-RNAi vector into the cerebellar an/age of a 3-day-old embryo allowed knockdown of MCT8 in Purkinje cell precursors. This resulted in the downregulation of the thyroid hormone-responsive gene ROR alpha and the Purkinje cell-specific differentiation marker LHX1/5 at day 6. MCT8 knockdown also results in a smaller and less complex dendritic tree at day 18 suggesting a pivotal role of MCT8 for cell-autonomous Purkinje cell maturation. Early administration of the thyroid hormone analogue 3,5,3'-triiodothyroacetic acid partially rescued early Purkinje cell differentiation. MCT8-deficient Purkinje cells also induced non-autonomous effects as they led to a reduced granule cell precursor proliferation, a thinner external germinal layer and a loss of PAX6 expression. By contrast, at day 18, the external germinal layer thickness was increased, with an increase in presence of Axonin-1-positive post-mitotic granule cells in the initial stage of radial migration. The concomitant accumulation of presumptive migrating granule cells in the molecular layer, suggests that inward radial migration to the internal granular layer is stalled. In conclusion, early MCT8 deficiency in Purkinje cells results in both cell-autonomous and non-autonomous effects on cerebellar development and indicates that MCT8 expression is essential from very early stages of development, providing a novel insight into the ontogenesis of the Allan-Herndon-Dudley syndrome.