Dicer is Required for Proliferation, Viability, Migration and Differentiation in Corticoneurogenesis

In mice, microRNAs (miRNAs) are required for embryonic viability, and previous reports implicate miRNA participation in brain cortical neurogenesis. Here, we provide a more comprehensive analysis of miRNA involvement in cortical brain development. To accomplish this we used mice in which Dicer, the RNase III enzyme necessary for canonical miRNA biogenesis, is depleted from Nestin-expressing progenitors and progeny cells. We systematically assessed how Dicer depletion impacts proliferation, cell death, migration and differentiation in the developing brain. Using markers for proliferation and in vivo labeling with thymidine analogs, we found reduced numbers of proliferating cells, and altered cell cycle kinetics from embryonic day 15.5 (E15.5). Progenitor cells were distributed aberrantly throughout the cortex rather than restricted to the ventricular and subventricular zones. Activated Caspase3 was elevated, reflecting increased cortical cell death as early as E15.5. Cajal-Retzius-positive cells were more numerous at E15.5 and were dysmorphic relative to control cortices. Consistent with this, Reelin levels were enhanced. Doublecortin and Rnd2 were also increased and showed altered distribution, supporting a strong regulatory role for miRNAs in both early and late neuronal migration. In addition, GFAP staining at E15.5 was more intense and disorganized throughout the cortex with Dicer depletion. These results significantly extend earlier works, and emphasize the impact of miRNAs on neural progenitor cell proliferation, apoptosis, migration, and differentiation in the developing mammalian brain.