Vancamp Pieter, Deprez Marie-Anne, Remmerie Michiel, Darras Veerle M
Laboratory of Comparative Endocrinology, Department of Biology, KU Leuven, B-3000 Leuven, Belgium.
Laboratory of Comparative Endocrinology, Department of Biology, KU Leuven, B-3000 Leuven, Belgium
J Neurosci. 2017 Nov 29;37(48):11616-11631. doi: 10.1523/JNEUROSCI.1917-17.2017. Epub 2017 Nov 6.
Thyroid hormones (THs) are essential for establishing layered brain structures, a process called corticogenesis, by acting on transcriptional activity of numerous genes. In humans, deficiency of the monocarboxylate transporter 8 (MCT8), involved in cellular uptake of THs before their action, results in severe neurological abnormalities, known as the Allan-Herndon-Dudley syndrome. While the brain lesions predominantly originate prenatally, it remains unclear how and when exactly MCT8 dysfunction affects cellular processes crucial for corticogenesis. We investigated this by inducing RNAi vector-based knockdown of MCT8 in neural progenitors of the chicken optic tectum, a layered structure that shares many developmental features with the mammalian cerebral cortex. MCT8 knockdown resulted in cellular hypoplasia and a thinner optic tectum. This could be traced back to disrupted cell-cycle kinetics and a premature shift to asymmetric cell divisions impairing progenitor cell pool expansion. Birth-dating experiments confirmed diminished neurogenesis in the MCT8-deficient cell population as well as aberrant migration of both early-born and late-born neuroblasts, which could be linked to reduced reelin signaling and disorganized radial glial cell fibers. Impaired neurogenesis resulted in a reduced number of glutamatergic and GABAergic neurons, but the latter additionally showed decreased differentiation. Moreover, an accompanying reduction in untransfected GABAergic neurons suggests hampered intercellular communication. These results indicate that MCT8-dependent TH uptake in the neural progenitors is essential for early events in corticogenesis, and help to understand the origin of the problems in cortical development and function in Allan-Herndon-Dudley syndrome patients. Thyroid hormones (THs) are essential to establish the stereotypical layered structure of the human forebrain during embryonic development. Before their action on gene expression, THs require cellular uptake, a process facilitated by the TH transporter monocarboxylate transporter 8 (MCT8). We investigated how and when dysfunctional MCT8 can induce brain lesions associated with the Allan-Herndon-Dudley syndrome, characterized by psychomotor retardation. We used the layered chicken optic tectum to model cortical development, and induced MCT8 deficiency in neural progenitors. Impaired cell proliferation, migration, and differentiation resulted in an underdeveloped optic tectum and a severe reduction in nerve cells. Our data underline the need for MCT8-dependent TH uptake in neural progenitors and stress the importance of local TH action in early development.
甲状腺激素（THs）通过作用于众多基因的转录活性，对于建立分层的脑结构（即皮质发生过程）至关重要。在人类中，参与THs作用前细胞摄取的单羧酸转运体8（MCT8）缺乏会导致严重的神经异常，即艾伦 - 赫恩登 - 达德利综合征。虽然脑部病变主要在产前发生，但目前尚不清楚MCT8功能障碍究竟如何以及何时影响对皮质发生至关重要的细胞过程。我们通过在鸡视顶盖的神经祖细胞中诱导基于RNAi载体的MCT8敲低来研究这一问题，视顶盖是一种分层结构，与哺乳动物大脑皮层具有许多发育特征。MCT8敲低导致细胞发育不全和视顶盖变薄。这可以追溯到细胞周期动力学的破坏以及过早转变为不对称细胞分裂，从而损害祖细胞池的扩张。出生时间标记实验证实，MCT8缺陷细胞群体中的神经发生减少，以及早期和晚期出生的神经母细胞的异常迁移，这可能与Reelin信号减少和放射状胶质细胞纤维紊乱有关。神经发生受损导致谷氨酸能和γ-氨基丁酸能神经元数量减少，但后者还表现出分化减少。此外，未转染的γ-氨基丁酸能神经元数量随之减少，表明细胞间通讯受阻。这些结果表明，神经祖细胞中依赖MCT8的TH摄取对于皮质发生的早期事件至关重要，并有助于理解艾伦 - 赫恩登 - 达德利综合征患者皮质发育和功能问题的起源。甲状腺激素（THs）对于在胚胎发育期间建立人类前脑的典型分层结构至关重要。在其对基因表达起作用之前，THs需要细胞摄取，这一过程由TH转运体单羧酸转运体8（MCT8）促进。我们研究了功能失调的MCT8如何以及何时能够诱发与艾伦 - 赫恩登 - 达德利综合征相关的脑部病变，该综合征的特征为精神运动发育迟缓。我们利用分层的鸡视顶盖来模拟皮质发育，并在神经祖细胞中诱导MCT8缺乏。细胞增殖、迁移和分化受损导致视顶盖发育不全和神经细胞严重减少。我们的数据强调了神经祖细胞中依赖MCT8的TH摄取的必要性，并强调了局部TH作用在早期发育中的重要性。
