N-myc is a key switch regulating the proliferation cycle of postnatal cerebellar granule cell progenitors

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.

Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4

“…We next examined the expression of Nmyc by immunohistochemical analysis of tumor tissue. Nmyc is known to be regulated by SHH and to mediate its effects on proliferation (33). AMD3100 had no effect compared with vehicle controls (Fig.…”

Notch/Hes signaling and miR-9 engage in complex feedback interactions controlling neural progenitor cell proliferation and differentiation

“…A recent publication suggested a role for miR-9 in regulating postnatal cerebellar growth 48 . This study originated from the observation that neonatal loss of N-Myc leads to reduced cerebellar mass due to a decrease in granule neuron progenitor proliferation.…”

“…This study originated from the observation that neonatal loss of N-Myc leads to reduced cerebellar mass due to a decrease in granule neuron progenitor proliferation. Follow-up experiments revealed that N-Myc is a negative regulator of miR-9, and that overexpression of miR-9 inhibits proliferation of granule neuron progenitors 48 . Again, it would be interesting to assess whether miR-9 and Notch interact with each other with regard to cortical and cerebellar progenitor cell expansion.…”

Sperm RNA elements as markers of health

“…Ingenuity Pathway Analysis (IPA) [Krämer et al 2014] highlighted MYCN (V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog) as an upstream regulator of 9 genes, EEF1A1, EEF1G, EEF2, EIF4G2, RPL29, RPL3, RPL37A, RPL41, and RPS24, in the cluster (p-value of overlap: 5.13E-13). MYCN is an oncogene implicated in many types of cancers, including neuroblastoma, non-small cell lung cancer, and prostate cancer [Boon et al 2001;Lee et al 2016;Ma et al 2015;Zhang et al 2016]. This transcript is highly expressed in testis (Human Protein Atlas (HPA): 5.1 transcripts per million (TPM), GTEx Portal: 3.1 RPKM; Figure 7) [Uhlén et al 2015], although the HPA classifies MYCN as a placentaenhanced transcript.…”