The functions of the imprinted miR379-410 cluster during neuronal migration in the developing telencephalon

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Neuronal migration disorders can cause severe malformations of the brain such as, in the worst case, lissencephaly with complete loss of gyrie. Children with lissencephaly are typically severely mentally retarded, among other symptoms. Whereas it was assumed in the past that neuronal migration disorders are irreversible and therefore the diseases caused by these disorders are incurable new studies using the mouse as model have shown that it is possible, in principle, to rescue neuronal migration disorders postnatally. It is essential to understand the molecular mechanisms that drive neuronal migration to be able to develop therapies for these disorders in the future.The microRNA (miRNA) cluster miR379-410 consists of 38 miRNAs that are co-expressed in the brain and regulate different aspects of neurogenesis. We have shown recently that three miRNAs of the cluster (miR-369-3p, -496, -543) regulate the expression of N-cadherin in an additive manner and that these miRNAs control neuronal migration in the developing neocortex, among other functions. Their co-expression prompted us to hypothesize that more miRNAs of that cluster than the ones we have studied regulate neuronal migration. A bioinformatic analysis of the predicted target genes of all miRNAs of the cluster revealed a significant enrichment for genes functionally related to neuronal migration for an additional eight miRNAs of the miR379-410 cluster. Moreover, according to the bioinformatic analysis each of the predicted target genes will likely be bound by several miR379-410 cluster miRNAs suggesting an additive or synergistic effect of regulation. Among those predicted target genes are several that are causative for the severe neuronal migration disorder lissencephaly, namely Doublecortin (Dcx), Lissencephaly 1 (Lis1 or Pafah1b1) and arista related homeobox (Arx). In this project we aim at characterizing which of the miR379-410 cluster miRNAs regulate neuronal migration, which genes these miRNAs target and which of these target genes are important effectors of miRNA function.