A Transgenic Approach to Identify Thyroxine Transporter-Expressing Structures in Brain Development
A Transgenic Approach to Identify Thyroxine Transporter-Expressing Structures in Brain Development
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DOI：
10.1111/j.1365-2826.2011.02216.x
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发表时间：
2011-12-01
影响因子：
3.2
通讯作者：
Schwaninger, M.
中科院分区：
文献类型：
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作者：
Lang, M. -F.;Salinin, S.;Schwaninger, M.
转运蛋白在甲状腺激素代谢中至关重要。甲状腺素 (T4) 通过溶质载体有机阴离子转运蛋白 1c1 (SLCO1C1、OATP14) 转运至成人大脑，在那里 T4 转化为 3,5,3'-三碘甲状腺原氨酸 (T3)。在成人中，SLCO1C1 在两种脑屏障结构中表达：血脑屏障 (BBB) 和脉络丛。然而，当 BBB 尚未完全形成时，人们对 T4 在发育中的大脑中如何运输知之甚少。我们采用细菌人工染色体重组技术来产生在 Slco1c1 位点携带 Cre 重组酶的转基因小鼠（Slco1c1-Cre 小鼠）。在 Slco1c1-Cre 小鼠中，Cre 在先前报道的成人 SLCO1C1 的位点表达。为了追踪发育过程中 Cre 的表达，我们将 Slco1c1-Cre 转基因小鼠与 Rosa26 报告小鼠杂交。 β-半乳糖苷酶染色显示各种大脑结构的神经元（例如皮质层 2/3 和海马）中存在 Cre 活性，表明大脑发育过程中存在短暂的 Slco1c1 表达。在胚胎第 15 天，SLCO1C1 在与 TBR2（神经元祖细胞标记）相同的位点表达。在发育过程中表达 SLCO1C1 的神经元可能对 T4 敏感。为了支持这一假设，对母鼠进行丙硫氧嘧啶治疗引起的低甲状腺素血症减少了新生 Slco1c1-Cre/Rosa26 小鼠皮质层 2/3 中 β-半乳糖苷酶阳性神经元的数量。总之，通过生成 Slco1c1-Cre 转基因小鼠，我们证明了 SLCO1C1 在大脑发育过程中的神经元细胞谱系中表达。 SLCO1C1 的表达可能是特定神经元群体对低甲状腺素血症异常敏感的基础。
Transporters are essential in thyroid hormone metabolism. Thyroxine (T4) is transported by solute carrier organic anion transporter 1c1 (SLCO1C1, OATP14) into the adult brain, where T4 is converted to 3,5,3'-triiodothyronine (T3). In adults, SLCO1C1 expression is found in two brain barrier structures: the bloodbrain barrier (BBB) and choroid plexus. However, little is known about how T4 is transported in the developing brain, when the BBB is not yet completely formed. We employed bacterial artificial chromosome recombineering to generate transgenic mice carrying Cre recombinase in the Slco1c1 locus (Slco1c1-Cre mice). In Slco1c1-Cre mice Cre was expressed at the sites that have been previously reported for SLCO1C1 in adults. To trace Cre expression during development, we crossed Slco1c1-Cre transgenic mice with Rosa26 reporter mice. beta-galactosidase staining showed Cre activity in neurones of various brain structures, such as cortical layer 2/3 and the hippocampus, suggesting transient Slco1c1 expression during brain development. At embryonic day15, SLCO1C1 was expressed at the same site as TBR2, a marker of neuronal progenitors. Neurones that express SLCO1C1 during their development could be T4 sensitive. In support of this hypothesis, hypothyroxinaemia induced by propylthiouracil treatment of dams decreased the number of beta-galactosidase-positive neurones in cortical layer 2/3 of newborn Slco1c1-Cre/Rosa26 mice. In conclusion, by generating Slco1c1-Cre transgenic mice, we demonstrated that SLCO1C1 is expressed in the neuronal cell lineage during brain development. Expression of SLCO1C1 may underlie the extraordinary sensitivity of specific neuronal populations to hypothyroxinaemia.