Importin-8 could cause CAE/JME by delaying early neuroblast migration

Abstract : Childhood Absence Evolving to Juvenile Myoclonic Epilepsy (CAE/JME) is an uncommon form of genetic generalized epilepsy that appears as absence in childhood and evolves into generalized tonic–clonic seizures with myoclonic jerks during adolescence. In some family of patients affected by CAE/JME, mutations have been observed in the gene encoding for the transport protein importin-8 (IPO8).
IPO8 could be at the origin of CAE/JME via its role in the transport of its targets (like Ago-2, Smad4, c-Jun). RT-qPCR has shown that IPO8 mRNA is expressed at all ages with no big difference in expression level. Using ISH, a clear expression of mIPO8 mRNA was observed in the sub-ventricular/ventricular zone (SVZ/VZ), the cortical plate (CP) and the ganglionic eminences (GE) of developing brain at E14. Both SVZ/VZ and GE are the “neurogenic niches” that generate glutamatergic and GABAergic neurons respectively. The implication of IPO8 in the generation of “glutamatergic neurons” was investigated by In Utero electroporation (IUE) and MGE Electroporation. Using shRNA, we observed that after 3 days, “glutamatergic neuroblasts” do not reach the CP in contrast to the control condition. This effect can be rescued by the co-expression of a form of IPO8 that is resistant to the shRNA. When overexpressing the pathological forms of hIPO8, but not a variant, migration of “glutamatergic neuroblasts” was also impaired. However, when the observation is made later, i.e. at P5, we observed that the neuroblasts finally reach their correct layer in the cortex, suggesting IPO8 only delayed but not blocked migration. Moreover, shRNA against IPO8 mRNA lead to alteration of interneurons (GABAergic neurons) migration same to overexpression of one mutated form of IPO8.
Conclusion : IPO8 is expressed in mouse brain during development. It shows a clear expression during embryogenesis in the “neurogenic niches”. Moreover, IPO8 modulates neuroblasts (radial and tangential) migration in the developing brain. So, abnormal brain development due to IPO8 mutations could be at the origin of CAE/JME.