Leibniz Institute on Aging/Fritz Lipmann Institute, 07745 Jena, Germany.
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
Cereb Cortex. 2022 Jan 10;32(2):329-341. doi: 10.1093/cercor/bhab211.
Cortical interneuron neurogenesis is strictly regulated and depends on the presence of thyroid hormone (TH). In particular, inhibitory interneurons expressing the calcium binding protein Parvalbumin are highly sensitive toward developmental hypothyroidism. Reduced numbers of Parvalbumin-positive interneurons are observed in mice due to the combined absence of the TH transporters Mct8 and Oatp1c1. To unravel if cortical Parvalbumin-positive interneurons depend on cell-autonomous action of Mct8/Oatp1c1, we compared Mct8/Oatp1c1 double knockout (dko) mice to conditional knockouts with abolished TH transporter expression in progenitors of Parvalbumin-positive interneurons. These conditional knockouts exhibited a transient delay in the appearance of Parvalbumin-positive interneurons in the early postnatal somatosensory cortex while cell numbers remained permanently reduced in Mct8/Oatp1c1 dko mice. Using fluorescence in situ hybridization on E12.5 embryonic brains, we detected reduced expression of sonic hedgehog signaling components in Mct8/Oatp1c1 dko embryos only. Moreover, we revealed spatially distinct expression patterns of both TH transporters at brain barriers at E12.5 by immunofluorescence. At later developmental stages, we uncovered a sequential expression of first Oatp1c1 in individual interneurons and then Mct8 in Parvalbumin-positive subtypes. Together, our results point to multiple cell-autonomous and noncell-autonomous mechanisms that depend on proper TH transport during cortical interneuron development.
皮质中间神经元的神经发生受到严格调控，并且依赖于甲状腺激素（TH）的存在。特别是，表达钙结合蛋白 Parvalbumin 的抑制性中间神经元对发育性甲状腺功能减退非常敏感。由于缺乏 TH 转运体 Mct8 和 Oatp1c1，小鼠中观察到 Parvalbumin 阳性中间神经元的数量减少。为了揭示皮质 Parvalbumin 阳性中间神经元是否依赖于 Mct8/Oatp1c1 的细胞自主作用，我们比较了 Mct8/Oatp1c1 双敲除（dko）小鼠与在 Parvalbumin 阳性中间神经元祖细胞中消除 TH 转运体表达的条件性敲除小鼠。这些条件性敲除小鼠在早期出生后体感皮层中出现 Parvalbumin 阳性中间神经元时表现出短暂的延迟，而 Mct8/Oatp1c1 dko 小鼠中的细胞数量则永久性减少。通过对 E12.5 胚胎大脑进行荧光原位杂交，我们仅在 Mct8/Oatp1c1 dko 胚胎中检测到 sonic hedgehog 信号成分的表达减少。此外，我们通过免疫荧光在 E12.5 时在大脑屏障上揭示了两种 TH 转运体的空间不同表达模式。在稍后的发育阶段，我们发现首先在个别中间神经元中表达 Oatp1c1，然后在 Parvalbumin 阳性亚型中表达 Mct8。总之，我们的结果表明，在皮质中间神经元发育过程中，存在多种依赖于适当 TH 转运的细胞自主和非细胞自主机制。
