Progressive effects ofN-mycdeficiency on proliferation, neurogenesis, and morphogenesis in the olfactory epithelium

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Abstract

N-mycbelongs to themycproto-oncogene family, which is involved in numerous cellular processes such as proliferation, growth, apoptosis, and differentiation. Conditional deletion ofN-mycin the mouse nervous system disrupted brain development, indicating thatN-mycplays an essential role during neural development. How the development of the olfactory epithelium and neurogenesis within are affected by the loss ofN-mychas, however, not been determined. To address these issues, we examined anN-mycFoxg1Creconditional mouse line, in whichN-mycis depleted in the olfactory epithelium. First changes inN-mycmutants were detected at E11.5, with reduced proliferation and neurogenesis in a slightly smaller olfactory epithelium. The phenotype was more pronounced at E13.5, with a complete lack ofHes5-positive progenitor cells, decreased proliferation, and neurogenesis. In addition, stereological analyses revealed reduced cell size of post-mitotic neurons in the olfactory epithelium, which contributed to a smaller olfactory pit. Furthermore, we observed diminished proliferation and neurogenesis also in the vomeronasal organ, which likewise was reduced in size. In addition, the generation of gonadotropin-releasing hormone neurons was severely reduced inN-mycmutants. Thus, diminished neurogenesis and proliferation in combination with smaller neurons might explain the morphological defects in theN-mycdepleted olfactory structures. Moreover, our results suggest an important role forN-mycin regulating ongoing neurogenesis, in part by maintaining theHes5-positive progenitor pool. In summary, our results provide evidence thatN-mycdeficiency in the olfactory epithelium progressively diminishes proliferation and neurogenesis with negative consequences at structural and cellular levels.

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