OTHR-19. Disordered cell migration in the cerebral cortex caused by Lin28A overexpression and Wnt pathway activation in neural precursor cells

Abstract

LIN28A overexpression and mutations of the Wnt pathway gene CTNNB1 have been described in rare malignant brain tumors of early childhood. In order to investigate the interplay of the oncogenic proteins Lin28A and Ctnnb1 during embryonal brain development, we overexpressed these components in neural progenitor cells in vivo. The sole overexpression of either Lin28A, stabilized Ctnnb1 (Ctnnb1Δex3) or the combination of both in hGFAP-positive forebrain precursor cells did not lead to brain tumor formation but resulted in distinct phenotypes in the cerebral cortex during embryonal development. The hGFAP-cre::IsI-Lin28A (GL) mouse model showed transiently increased proliferation in the cerebral ventricular zone and proper isocortical layering. hGFAP-cre::Ctnnb1Δex3fl/+ (GB) and hGFAP-cre::Ctnnb1Δex3fl/+::IsI-Lin28A (GBL) mice developed a hydrocephalus and showed disturbed cortical layering. GB mice displayed cerebral hypoplasia with a thinned cortex, while the GBL cortices showed variable thickness. Immunostainings with the pial marker Laminin and dendritic marker Map2c revealed a porous pia mater and aggregations of neurons above the pial border in the GBL model at embryonal day 14 (E14.5). At later embryonal stage (E18.5), the GBL model showed also large blood vessels located in deeper cortical layers. Proteome analyses of GB and GBL cortices revealed decreased abundance of the Lissencephaly associated component Reelin-receptor Lrp8 compared to hGFAP-cre control mice. Additionally, we found 92 proteins, which were altered specifically in the GBL mouse model. These results indicate that the co-expression of Lin28A and Ctnnb1Δex3 in neural precursor cells does not lead to brain tumor formation but results in neuronal migration disturbances with ectopic neurons in the subarachnoid area. Whereas the GB phenotype is reminiscent of human lissencephaly type I, GBL brain morphology showed similarities to neuronal overmigration observed in the migration disorder of human Cobblestone (Type II) Lissencephaly.