Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation
Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation
复制标题
DOI：
10.1523/jneurosci.1545-17.2017
复制
发表时间：
2018-01-31
影响因子：
5.3
通讯作者：
Hoshino, Mikio
中科院分区：
文献类型：
--
作者：
Owa, Tomoo;Taya, Shinichiro;Hoshino, Mikio
小脑颗粒细胞前体细胞（GCPs）和颗粒细胞（GCs）是研究神经元发育的良好模型。在这里，我们报告转录因子骨髓异位病毒整合位点1同源物（Meis 1）在调节小鼠GC发育中发挥关键作用。我们发现Meis 1在发育过程中在小脑的GC谱系细胞和星形胶质细胞中表达。在GC谱系中特异性地靶向破坏Meis 1基因导致小脑较小，小叶紊乱。Meis 1的敲除/敲除（KO）实验和体外测定表明，Meis 1结合Pax 6的上游序列以增强其在GCPs/GC中的转录，并且还表明Meis 1-Pax 6级联在发育期间调节GCPs/GC的形态。在条件KO（cKO）小脑，观察到许多Atoh 1阳性GCP异位在内部外部颗粒层（EGL）和一个类似的现象，观察到在培养的小脑切片与骨形态发生蛋白（BMP）抑制剂。此外，Smad蛋白的表达和Smad磷酸化在cKO小脑和Meis 1敲低的GCPs小脑中严重减少。在用Pax 6敲低载体电穿孔的小脑切片中也观察到磷酸化Smad的减少。由于已知BMP信号传导诱导GCPs中Atoh 1降解，因此这些发现表明Meis 1-Pax 6途径增加Smad蛋白的表达以上调BMP信号传导，导致内EGL中Atoh 1降解，这有助于从GCPs分化为GC。因此，这项工作揭示了Meis 1在GC发育中的关键功能，并深入了解了神经祖细胞神经分化的分子机制。
Cerebellar granule cell precursors (GCPs) and granule cells (GCs) represent good models to study neuronal development. Here, we report that the transcription factor myeloid ectopic viral integration site 1 homolog (Meis1) plays pivotal roles in the regulation of mouse GC development. We found that Meis1 is expressed in GC lineage cells and astrocytes in the cerebellum during development. Targeted disruption of the Meis1 gene specifically in the GC lineage resulted in smaller cerebella with disorganized lobules. Knock-down/knock-out (KO) experiments for Meis1 and in vitro assays showed that Meis1 binds to an upstream sequence of Pax6 to enhance its transcription in GCPs/GCs and also suggested that the Meis1-Pax6 cascade regulates morphology of GCPs/GCs during development. In the conditional KO (cKO) cerebella, many Atoh1-positive GCPs were observed ectopically in the inner external granule layer (EGL) and a similar phenomenon was observed in cultured cerebellar slices treated with a bone morphogenic protein (BMP) inhibitor. Furthermore, expression of Smad proteins and Smad phosphorylation were severely reduced in the cKO cerebella and Meis1-knock-down GCPs cerebella. Reduction of phosphorylated Smad was also observed in cerebellar slices electroporated with a Pax6 knock-down vector. Because it is known that BMP signaling induces Atoh1 degradation in GCPs, these findings suggest that the Meis1-Pax6 pathway increases the expression of Smad proteins to upregulate BMP signaling, leading to degradation of Atoh1 in the inner EGL, which contributes to differentiation from GCPs to GCs. Therefore, this work reveals crucial functions of Meis1 in GC development and gives insights into the general understanding of the molecular machinery underlying neural differentiation from neural progenitors.