Hmga2 promotes neural stem cell self-renewal in young, but not old, mice by reducing p16Ink4a and p19Arf expression

By J. Nishino, Injune Kim, K. Chada, S. Morrison. Cell, 2008

638 citations recorded by the source corpus.

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.

Subfields: Developmental Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3508d4c77662b071609a8fc611d3dd6d4f1f57e2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Developmental Neuroscience

1. Shenghui He
2. S. Morrison

In Genetics

1. S. Morrison

In Molecular Biology

1. Shenghui He
2. Daisuke Nakada
3. S. Morrison
4. S. Piccolo
5. M. Jansson
6. A. Alimonti
7. Marcus E. Peter
8. J. Kohli

Citations in the corpus

• The role of let-7 in cell differentiation and cancer. (2010, background): “2008), and a truncated HMGA2 has been shown to correlate with larger body size (Nishino et al. 2008) and reduced adult human height (Lettre et al.”
• MicroRNA control of signal transduction (2010, background): “By taming proto-oncogenic signalling, let-7 may oppose cancer, but it may also contribute to the decline of normal stem cell function and tissue renewal associated with agein”
• Mechanisms of stem cell self-renewal. (2009, background): “However, Hmga2 expression is extinguished in old adult neural stem cells (Nishino et al. 2008).”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Owing to INK4A/ARF forming a barrier to reprogramming in vitro, it has been suggested that transient silencing of the locus during cellular reprogramming could be an effective approach for regenerative medicine in old individuals without increasing risk of malignancy (204).”
• MicroRNA and cancer (2012, background): “…HMGA2 is a repressor of the key inducers of senescence p16 and p19, products of the INK4A locus often mutated in cancers (Lee and Dutta, 2007; Nishino et al., 2008; Sherr, 1996). p16 is a specific inhibitor of CDK4/6 and is also repressed by miR24, which is down-regulated during replicative…”