Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency

The RNA binding protein RBM4 promotes neuronal differentiation and radial migration of cortical progenitors. To investigate its role in development, we generated constitutive homozygous Rbm4a/Rbm4b double-knockout (dKO) mice, which exhibited foliation defects in cerebellar lobules VI-VII and altered behaviors, including delayed motor learning and reduced anxiety. Rbm4 double knockout impaired proliferation and differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells. These features 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.