Chromosomal Mosaicism in Neural Stem Cells

Abstract

Neural stem and progenitor cells (referred to here as NSCs), located in the proliferative zones of embryonic brains, can be seen undergoing mitosis at the ventricular surface. Mitotic NSCs can be arrested in metaphase and chromosome "spreads" produced to reveal their chromosomal complement. Studies in mice and humans have revealed a prominent developmental presence of aneuploid NSCs, whereas other chromosomal defects, such as interchromosomal translocations and partial chromosomal deletions/insertions, are extremely rare (1,2). Aneuploidy is defined as the loss or gain of whole chromosomes, resulting in cells that deviate from the normal diploid number of chromosomes (46 in humans, 40 in mice). In NSCs, aneuploidy can occur as a result of mis-segregation during mitosis, through events such as lagging chromosomes, supernumerary centrosomes, and nondisjunction events (3). The percentage of aneuploid NSCs can be altered by in vivo and in vitro growth conditions as well as through genetic deletion of genes involved in DNA surveillance and repair (1,4). Aneuploidy can be detected by classical cytogenetic methods such as counting the number of chromosomes visualized by DNA dyes (e.g., 4,6-diamidino-2-phenylindole) by using standard light or fluorescence microscopy. Precise chromosome identification is much more difficult: classical methods using banding patterns or size to assign identity are very time consuming even under ideal conditions, and they are notoriously difficult in mice, which often have ambiguous banding patterns and acrocentric chromosomes. A comparatively new technique that allows the unambiguous identification of chromosomes in mice and humans is "spectral karyotyping" or SKY, developed by Ried et al. at the National Institutes of Health for the study of cancer cells (5). This technique uses chromosomal "paints" that are hybridized to chromosome spreads to produce a distinct spectral output for each chromosome. SKY offers superior speed and sensitivity in its ability to detect many types of chromosomal defects, including deletions, insertions, translocations, and aneuploidy.

LINE-1 Elements in Structural Variation and Disease

“…The observed increase in L1 DNA copy number in the brain suggests elevated levels of endogenous L1 retrotransposition in brain. However, other non-mutually-exclusive mechanisms must be considered when accounting for these L1 copy number differences (195, 251). Indeed, formal proof of endogenous L1 retrotransposition in brain will require the characterization of new L1 insertions from individual neurons.…”

Murine and human very small embryonic‐like cells: A perspective

“…We further conducted a karyotypic analysis that revealed an aneuploid karyotype in the majority of purified VSEL cells by fluorescence in situ hybridization. Although aneuploidy has long been associated with cancer, it has recently been observed in cultured pluripotent and neuronal stem cells as well as normal neuronal progenitors and primary cells from blastocysts, so that the tendency to generate aneuploid cells may be a normal feature of regenerative systems (23)(24)(25)(26). Even so, the aneuploid pro- ducts themselves are unlikely to make a long-term contribution to regeneration, and it is unsurprising that these cells are unable to expand in vitro.…”

Neuronal DNA content variation (DCV) with regional and individual differences in the human brain

“…Neural aneuploidy occurs to a similar extent in both neurons and glia (Rehen et al, 2005), is found phylogenetically from fish through humans (Kingsbury et al, 2006; Peterson et al, 2008; Rajendran et al, 2007; Rehen et al, 2001; Rehen et al, 2005; Yurov et al, 2005), and is present throughout the neuraxis, with no obviously distinguishable neuroanatomical patterns (Rehen et al, 2001; Rehen et al, 2005; Westra et al, 2008). Aneuploidy represents the first, proven form of DNA sequence alteration(s) present in normal neural cells, while making it likely that other phenomena associated with “genomic instability” could also be present.…”