miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex

Abstract

Neurogenesis during the development of the mammalian cerebral cortex involves a switch of neural stem and progenitor cells from proliferation to differentiation. To explore the possible role of microRNAs (miRNAs) in this process, we conditionally ablated Dicer in the developing mouse neocortex using Emx1-Cre, which is specifically expressed in the dorsal telencephalon as early as embryonic day (E) 9.5. Dicer ablation in neuroepithelial cells, which are the primary neural stem and progenitor cells, and in the neurons derived from them, was evident from E10.5 onwards, as ascertained by the depletion of the normally abundant miRNAs miR-9 and miR-124. Dicer ablation resulted in massive hypotrophy of the postnatal cortex and death of the mice shortly after weaning. Analysis of the cytoarchitecture of the Dicer-ablated cortex revealed a marked reduction in radial thickness starting at E13.5, and defective cortical layering postnatally. Whereas the former was due to neuronal apoptosis starting at E12.5, which was the earliest detectable phenotype, the latter reflected dramatic impairment of neuronal differentiation. Remarkably, the primary target cells of Dicer ablation, the neuroepithelial cells, and the neurogenic progenitors derived from them, were unaffected by miRNA depletion with regard to cell cycle progression, cell division, differentiation and viability during the early stage of neurogenesis, and only underwent apoptosis starting at E14.5. Our results support the emerging concept that progenitors are less dependent on miRNAs than their differentiated progeny, and raise interesting perspectives as to the expansion of somatic stem cells.

MicroRNAs and glioblastoma; the stem cell connection

“…This revealed altered brain morphogenesis in zebrafish, 40 and the absence of Dicer from dopaminergic neurons in mice leads to their progressive loss. 41 Loss of Purkinje cells of the cerebellum, 42 and neo-cortical neurons has also been described 43 indicating the importance of proper microRNA processing in brain development.…”

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells

“…Conditional disruption of Dicer in the developing cortex or other developing brain tissues by tissue-specific Cre results in a decreased number of neural progenitor cells (NPCs), increased apoptosis, and abnormal neuronal differentiation [17][18][19][20][21]. Although ablation of the microprocessor activity by Dgcr8 inactivation in developing brain leads to similar phenotypes, the phenotypic defects are significantly milder than those caused by Dicer inactivation [22].…”

miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

“…Approximately 50% of mammalian miRNAs are expressed in the brain (Krichevsky et al ., 2003; Somel et al ., 2011), many of which have critical roles in neurogenesis and neuronal development (Giraldez et al ., 2005; De Pietri Tonelli et al ., 2008). A number of hippocampal miRNAs regulate neuronal activity by targeting their downstream genes (Eacker et al ., 2011; Juhila et al ., 2011).…”