Abstract
N-myc plays an important role in early cerebellar development; however, the role of N-myc in postnatal cerebellar development is still unknown. In this study, inducible and reversible N-myc mouse models (NmycTRE/TRE:tTS and NmycEGFP/TRE:tTS) are used to regulate and track the expression of endogenous N-myc in vivo. Loss of N-myc at the neonatal stage results in reduced proliferation of granule cell precursors (GCPs) and reduced cerebellar volume/mass. Restoration of N-myc expression no later than postnatal day 4 can rescue the cerebellar developmental defect caused by the absence of N-myc after birth. During cerebellar postnatal development, N-myc acts as a key switch, regulating the proliferation cycle of postnatal granule cell progenitors. Loss of N-myc significantly impairs the Sonic hedgehog signalling pathway, and disrupts the expression of cell cycle effectors with a significant reduction of Ccnd2. More importantly, N-myc negatively regulates the expression of microRNA-9 during postnatal cerebellar development. Our findings demonstrate that over-expression of miR-9 can inhibit the proliferation of GCPs. The regulation of these factors by N-myc is at least partly responsible for the switch role of N-myc in the proliferation cycle of GCPs.
Highlights
N-myc plays an important role in early cerebellar development; the role of N-myc in postnatal cerebellar development is still unknown
In NmycTRE mice, a tetracycline response element (TRE) sequence was inserted into the first intron of the endogenous N-myc gene
In NmycTRE/TRE:transcriptional suppressor (tTS) mice, N-myc expression was dependent on the presence or absence of doxycycline (DOX)
Summary
N-myc plays an important role in early cerebellar development; the role of N-myc in postnatal cerebellar development is still unknown. Loss of N-myc in neuronal progenitor cells by use of a nestin-Cre transgene severely disrupts cerebellar development, resulting in a significantly smaller and disorganised cerebellum, and a significant reduction in granule cell numbers[5] These results indicate that N-myc may play an important role www.nature.com/scientificreports/. An inducible and reversible endogenous N-myc gene expression mouse model was developed[6], which provides an opportunity to explore the function of N-myc in a specific time window Using this model, we have shown that loss of N-myc after birth results in defective cerebellar development, a smaller cerebellum and a reduction of granule cell density[6]. The exact role of N-myc in postnatal cerebellar development and the underlying molecular mechanisms are still unclear
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