Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a and p19Arf Expression

Abstract

SUMMARY Stem cells persist throughout life in diverse tissues by undergoing self-renewing divisions. Self-renewal capacity declines with age, partly due to increasing p16Ink4a expression, but little is known about the mechanisms responsible for these changes. We discovered the Hmga2 transcriptional regulator was highly expressed in fetal neural stem cells but expression declined with age, partly due to increasing let-7b microRNA expression. Hmga2 deficiency reduced stem cell frequency and self-renewal throughout the central and peripheral nervous systems of fetal and young adult mice, but not old adult mice where it was no longer expressed. Hmga2 deficiency did not affect restricted neural progenitor proliferation. Hmga2 deficient fetal and young adult stem cells exhibited increased p16Ink4a and p19Arf expression, and deletion of p16Ink4a and/or p19Arf partially rescued their self-renewal. let-7b over-expression reduced Hmga2 expression and increased p16Ink4a/p19Arf expression. Changes in let-7b and Hmga2 expression during stem cell aging increase p16Ink4a/p19Arf expression and reduce self-renewal.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…Similarly, a study on human mammary epithelial cells (HMECS) identified several miRNAs that regulate p16 INK4a expression (Overhoff et al ., 2014) and suggested that they might target different components of PRC1 and PRC2. In addition, it has been shown that the miRNA let‐7 can downregulate HMGA2 levels and is responsible for the induction of p16 INK4a during the aging of adult stem cells (Nishino et al ., 2008). Here, we described an autoregulatory loop involving CBX7 and miR‐9 that could contribute to fine‐tune the induction of p16 INK4a during replicative senescence.…”

Regulation of microRNA expression by HMGA1 proteins

“…In fact, the block of the HMGA2 protein synthesis prevents thyroid cell transformation by acute murine retroviruses (Berlingieri et al, 1995). Very recently, it has been shown that HMGA2 promotes neural stem cell self-renewal in young mice reducing p16 and p19 (Nishino et al, 2008). Then, it is reasonable to hypothesize that the downregulation of miR-196a-2 leading to increased HMGA2 levels could represent a further mechanism by which HMGA1 overexpression can contribute to cell transformation.…”

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

“…Analysis of these data revealed that the majority of genes were expressed at similar levels between adult and aged samples, although 254 genes were differentially expressed (Figure 1a and Table S1; False Discovery Rate (FDR) < .05). As an initial confirmation of our dataset, we detected changes in Dlx2 and Let‐7b expression, which are misregulated in aged NSPCs (Nishino et al., 2008; Shi et al., 2017). Furthermore, many cell type‐specific genes were detected at comparable levels in adult and aged samples, indicating that the cellular composition of the neurospheres was unchanged with age (Figure S1A).…”

“…Igf2bp2 is expressed in embryonic cortical progenitors where it promotes neurogenesis at the expense of astrogenesis (Fujii et al., 2013), but its role in the postnatal SVZ has not been investigated. Igf2bp1 supports proliferation and prevents premature differentiation of embryonic cortical progenitors, but its expression is extinguished postnatally (Nishino et al., 2008). It is tempting to speculate that the role of Igf2bp1 in maintaining embryonic NSPC proliferation is superseded by Igf2bp2 in the postnatal SVZ, and that the combined decay of Igf2bp1/2 levels underlies the progressive decline of NSPC proliferation during postnatal life.…”

“…This age‐associated neurogenic decline appears to be caused both by a depletion in the NSPC pool of the aged niche (Ahlenius, Visan, Kokaia, Lindvall & Kokaia, 2009; Bouab, Paliouras, Aumont, Forest‐Berard & Fernandes, 2011; Corenblum et al., 2016; Enwere et al., 2004; Luo et al., 2006; Maslov, Barone, Plunkett & Pruitt, 2004; Molofsky et al., 2006; Stoll et al., 2011) and by the decreased capacity of the remaining NSPCs to sustain proliferation and neuronal differentiation, as revealed by in vitro studies (Ahlenius et al., 2009; Apostolopoulou et al., 2017; Corenblum et al., 2016; Daynac, Morizur, Chicheportiche, Mouthon & Boussin, 2016; Daynac et al., 2014; L'Episcopo et al., 2013; Shi et al., 2017; Zhu et al., 2014). NSPCs undergo cell autonomous age‐related changes that affect intracellular molecular pathways, including the altered expression of telomerase and cell cycle regulators, which have been linked to the decline in NSPC proliferation upon aging (Caporaso, Lim, Alvarez‐Buylla & Chao, 2003; Molofsky et al., 2006; Nishino, Kim, Chada & Morrison, 2008). Transcriptional analysis of the aged whole SVZ cell population (including NSPCs, differentiated cells and non‐neural cell types) identified several misregulated genes that are associated with NSPC proliferation and differentiation, suggesting that intrinsic gene expression changes in aged NSPCs can alter adult neurogenesis (Apostolopoulou et al., 2017; Shi et al., 2017).…”