C-myc and N-myc in the developing brain

Abstract

Murine knockouts (KO) of myc genes have provided substantial insight into not only their normal functions during development, but also shed light on their tumorigenic functions when they are misregulated. c-myc and N-myc genes both are essential neural stem and precursor cells (NSC) for normal mouse brain growth[1,2]. The fact that mutation of N-myc also causes microcephaly humans Feingold Syndrome[3], suggests common Myc-regulated pathways are at work during mouse and human brain growth. Earlier studies indicate that N-Myc drives brain growth by maintaining widespread domains of euchromatin [4] required for NSC proliferation and pluripotency. Such events may be locked in during tumorigenesis driving Myc-associated neuronal tumors such as neuroblastoma and medulloblastoma as N-Myc regulates global euchromatin neuroblastoma as well [5]. A substantial obstacle to understanding the respective functions of different myc genes neurogenesis is their redundancy and coexpression. To overcome these problems and explore Myc function brain development as well as tumorigenesis, here we generated a double KO (DKO) for c- and N-myc using nestin-cre. Overall brain growth is strongly impaired DKO mice, a phenotype associated with decreased cell cycling and migration of NSC, which are profoundly decreased number. Interestingly, the midbrain of DKO mice appeared unaffected by loss of c- and N-myc, suggesting that L-myc controls midbrain growth, while both c- and N-myc regulate fore- and hindbrain development (Figure ​(Figure1).1). Overall, N-myc is the main conductor of brain growth. Surprisingly, survival was not clearly affected by the loss of c- and N-myc NSC. Changes gene expression the DKO include downregulation of genes involved protein and nucleotide metabolism, mitosis, and chromatin structure as well as upregulation of genes associated with differentiation. Very few changes gene expression were observed the midbrain, further supporting the notion that c- and N-myc are dispensable for midbrain development. These are the first vivo studies of Myc regulation of gene expression the nervous system. Our findings suggest a model of neuronal tumorigenesis which excess myc aberrantly enforces a developmentally active chromatin state characterized by rapid cell cycling, hyperactive metabolism, and blocked differentiation. We refer the readers to the full text paper [6]. Figure 1. Model of regulation of brain architecture by the myc gene family.