Abstract
Neural Stem Cells (NSCs) are a distinct group of cells present in the embryonic and adult mammalian central nervous system (CNS) that are able to differentiate into neurons, astrocytes and oligodendrocytes. As NSC proliferation declines with age, factors that regulate this process need to be defined. To search for NSC regulatory factors, we performed a quantitative shotgun proteomics study that revealed that members of the High Mobility Group B (HMGB) family are highly expressed in NSCs. Using a neurosphere assay, we report the differential expression of HMGB 1, 2, 3, and 4 mRNAs in proliferating NSCs isolated from various time points during embryonic development, as well as the dynamic expression of HMGB1 and B2 mRNAs and proteins in differentiating embryonic NSCs. Expression of HMGB2 underwent the most dramatic changes during the developmental ages examined; as a result, we assessed its role in NSC proliferation and differentiation. We report the predominance of small diameter HMGB2-/- neurospheres in comparison to wild-type, which correlated with increased proliferation in these smaller HMGB2-/- neurospheres. Our data suggest that HMGB2 plays a regulatory role in NSC cell proliferation and maintenance pathways.
Highlights
During embryonic development, neuroepithelial cells in the cerebral cortex display characteristics of radial glial cells [1]
To gain insight into the molecular mechanisms regulating Neural Stem Cells (NSCs) proliferation, studies have focused on regulators of p16Ink4a expression, such as high mobility group protein A2 (HMGA2) [11], which is a member of the HMG superfamily of non-histone proteins found in the nuclei of mammalian cells that bind to nucleosomes and the minor groove of DNA in a sequence-independent manner [12,13,14]
HMG subfamily B (HMGB) mRNAs and proteins in NSCs A neurosphere formation assay was used to grow NSCs isolated from the brains of embryonic E12.5 C57BL/6 mice [4,5,6]
Summary
Neuroepithelial cells in the cerebral cortex display characteristics of radial glial cells [1]. Neural Stem Cells (NSCs) give rise to progenitor cells that differentiate Studies of these putative embryonic and adult NSCs have defined some of the mitogens that regulate NSC proliferation [4,5,6,7,8], but the precise molecular mechanisms underlying stem cell maintenance and self-renewal remain incompletely understood. To gain insight into the molecular mechanisms regulating NSC proliferation, studies have focused on regulators of p16Ink4a expression, such as high mobility group protein A2 (HMGA2) [11], which is a member of the HMG superfamily of non-histone proteins found in the nuclei of mammalian cells that bind to nucleosomes and the minor groove of DNA in a sequence-independent manner [12,13,14]. The Let7b-HMGA2 axis regulates p16Ink4a expression, which in turn controls NSC proliferation and self-renewal [16]
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