Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Columbia University in the City of New York, New York, US.
Commun Biol. 2023 Sep 5;6(1):910. doi: 10.1038/s42003-023-05294-z.
A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI-VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation-the intercrural fissure in particular-in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency.
神经生长因子信号与小脑叶片之间缺乏分子和功能联系。在这里，我们表明，两个编码 RNA 结合蛋白 RBM4 的同源基因的组成性敲除导致小鼠小脑 VI-VII 叶的叶片缺陷和运动学习延迟。此外，Rbm4 双敲除（dKO）的特征，包括小脑颗粒细胞分化受损和浦肯野细胞树突分支减少，类似于神经营养因子缺乏。RBM4 的缺失确实降低了脑源性神经营养因子（BDNF）。RBM4 促进了 BDNF 和全长 TrkB 的表达，表明 RBM4 参与了有效的 BDNF-TrkB 信号传导。最后，产前补充 TrkB 激动剂 7,8-二羟基黄酮可恢复 Rbm4dKO 小鼠新生小脑颗粒细胞的分化、浦肯野细胞树突复杂性和叶片形成——特别是在中间裂——并改善成年期的运动学习。这项研究提供了证据表明，产前激活 TrkB 信号可以改善由 BDNF 缺乏引起的小脑畸形。
