Stem Cells on the Brain

Abstract

Mutations that cause autosomal recessive primary microcephaly (MCPH), including MCPH1 through MCPH6, have provided insight into the normal programming that directs brain growth and defines ultimate brain size. The common denominator in these mutations is that they all manifest within neural stem and progenitor cells, decreasing their numbers at various stages of neurogenesis. Microcephalin (MCHP1) and abnormal spindlelike, microcephaly associated (MCPH5) have been the focus of most of the research. However, the recent discovery of microcephaly caused by mutation of the N-myc (also MYCN) proto-oncogene both in mice, where it was directed specifically to neural stem cells, and in the germ line in humans in Feingold syndrome has shed new light on the role of neural stem cells in brain growth. N-myc controls brain growth not only by regulating neural stem cell proliferation, but also through maintaining a neural stem cell identity at least in part via a mechanism involving global chromatin. Interestingly, along with microcephaly, mutation of N-myc also causes chromatin condensation in neural stem cells, while premature chromosome condensation (PCC) is observed with mutation of MCHP1. The fact that 2 genes required for brain growth are also essential for normal chromatin structure suggests that the global chromatin activity state of neural stem cells is a key factor in regulation of brain mass. In this review, we will focus on the links between neural stem cell chromatin and brain growth.