Abstract
AbstractA 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.
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference48 articles.
1. Lin, J. C. & Tarn, W. Y. RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing. J. Cell Biol. 193, 509–520 (2011).
2. Lin, J. C. et al. RBM4 promotes pancreas cell differentiation and insulin expression. Mol Cell Biol. 33, 319–327 (2013).
3. Lin, J. C. et al. Emerging role for RNA binding motif protein 4 in the development of brown adipocytes. Biochim. Biophys. Acta. 1843, 769–779 (2014).
4. Tarn, W. Y. et al. RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression. Mol. Biol. Cell. 10, 1676–1683 (2016).
5. Su, C. H. et al. RBM4 regulates neuronal differentiation of mesenchymal stem cells by modulating alternative splicing of pyruvate kinase M. Mol. Cell Biol. 37, e00466–16 (2017).