Abstract
Human MYCN is an oncogene amplified in neuroblastoma and many other tumors. Both human MYCN and mouse Mycn genes are important in embryonic brain development, but their functions in adult healthy nerve system are completely unknown. Here, with Mycn-eGFP mice and quantitative RT-PCR, we found that Mycn was expressed in specific brain regions of young adult mice, including subventricular zone (SVZ), subgranular zone (SGZ), olfactory bulb (OB), subcallosal zone (SCZ), and corpus callosum (CC). With immunohistochemistry (IHC), we found that many Mycn-expressing cells expressed neuroblast marker doublecortin (DCX) and proliferation marker Ki67. With Dcx-creER and Mki67-creER mouse lines, we fate mapped Dcx-expressing neuroblasts and Mki67-expressing proliferation cells, along with deleting Mycn from these cells in adult mice. We found that knocking out Mycn from adult neuroblasts or proliferating cells significantly reduced cells in proliferation in SVZ, SGZ, OB, SCZ, and CC. We also demonstrated that the Mycn-deficient neuroblasts in SGZ matured quicker than wild-type neuroblasts, and that Mycn-deficient proliferating cells were more likely to survive in SVZ, SGZ, OB, SCZ, and CC compared to wild type. Thus, our results demonstrate that, in addition to causing tumors in the nervous system, oncogene Mycn has a crucial function in neurogenesis and oligodendrogenesis in adult healthy brain.
Highlights
MYCN, the human gene encoding N-Myc, was first identified as an oncogene amplified in human neuroblastoma [1], a tumor characterized as having undifferentiated neuroblasts [2]
With MycnEGFP reporter mice [17], we found that Mycn is expressed in restricted regions in adult brain, such as subventricular zone (SVZ), subgranular zone (SGZ) of hippocampal dentate gyrus (DG), the two major sites for adult neurogenesis [18], and corpus callosum (CC) and subcallosal zone (SCZ), 1 3
We found that GFP was expressed in SVZ (Fig. 1a), SGZ (Fig. 1b), and olfactory bulb (OB) (Fig. 1c)
Summary
MYCN, the human gene encoding N-Myc, was first identified as an oncogene amplified in human neuroblastoma [1], a tumor characterized as having undifferentiated neuroblasts [2]. The expression level of MYCN correlates with the prognosis of neuroblastoma [3], and overexpression of human MYCN gene produces neuroblastoma in mice [4]. Mouse Mycn gene is expressed in embryonic and neonatal forebrains and hindbrains [11], and in embryonic eye, spinal cord, dorsal root ganglion (DRG) (spinal ganglia) and trigeminal ganglia (cranial ganglion) [12]. Mycn plays an important role in the proliferation and survival of embryonic sympathetic neuroblasts [15]. Mycn is highly functional in pluripotent cells as well, because overexpression of Mycn, along with Oct, Sox, and Klf, transforms mouse embryonic fibroblasts into induced pluripotent stem cells [16]
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