School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
Nat Commun. 2017 May 18;8:15079. doi: 10.1038/ncomms15079.
In the cerebellar cortex, Purkinje cells (PCs) receive signals from different inputs through their extensively branched dendrites and serve as an integration centre. Defects in the dendritic development of PCs thus disrupt cerebellar circuitry and cause ataxia. Here we report that specific inactivation of both Lhx1 and Lhx5 in postnatal PCs results in ataxic mutant mice with abnormal dendritic development. The PCs in the mutants have reduced expression of Espin, an F-actin cytoskeleton regulator. We show that Espin expression is transcriptionally activated by Lhx1/5. Downregulation of Espin leads to F-actin mislocalization, thereby impairing dendritogenesis and dendritic spine maturation in the PCs. The mutant PCs therefore fail to form proper synapses and show aberrant electrophysiological properties. By overexpressing Espin, we can successfully rescue the defects in the mutant PCs. Our findings suggest that Lhx1/5, through regulating Espin expression, control dendritogenesis and spine morphogenesis in postnatal PCs.
在小脑皮层中，浦肯野细胞 (PCs) 通过其广泛分支的树突接收来自不同输入的信号，并充当整合中心。因此，PCs 的树突发育缺陷会破坏小脑回路并导致共济失调。在这里，我们报告说，在出生后 PC 中特异性失活 Lhx1 和 Lhx5 会导致具有异常树突发育的共济失调突变小鼠。突变体中的 PCs 表达的 Espin 减少，Espin 是一种 F-肌动蛋白细胞骨架调节剂。我们表明，Lhx1/5 转录激活 Espin 的表达。Espin 的下调导致 F-肌动蛋白定位错误，从而损害 PCs 中的树突发生和树突棘成熟。因此，突变的 PCs 无法形成适当的突触，并表现出异常的电生理特性。通过过表达 Espin，我们可以成功挽救突变体 PC 中的缺陷。我们的发现表明，Lhx1/5 通过调节 Espin 的表达，控制出生后 PC 中的树突发生和棘突形态发生。
