Neural stem cell self-renewal

https://doi.org/10.1016/j.critrevonc.2007.06.004Get rights and content

Abstract

Two fundamental properties of stem cells are their ability to self-renew and to differentiate. Self-renewal is an integration of proliferation control with the maintenance of an undifferentiated state. Stem cell self-renewal is regulated by the dynamic interplay between transcription factors, epigenetic control, microRNA (miRNA) regulators, and cell-extrinsic signals from the microenvironment in which stem cells reside. Recent progress in defining specific roles for cell-intrinsic factors and extrinsic factors in regulating stem cell self-renewal starts to unfold the multilayered regulatory networks. This review focuses on cell-intrinsic regulators, including orphan nuclear receptor TLX, polycomb transcriptional repressor Bmi1, high-mobility-group DNA binding protein Sox2, basic helix-loop-helix Hes genes, histone modifying enzymes and chromatin remodeling proteins, and small RNA modulators, as well as cell-extrinsic signaling molecules, such as Wnt, Notch, Sonic hedgehog (Shh), TGFα, EGF, and FGF. Unraveling the mechanisms by which neural stem cells renew themselves will provide insights into both basic neurosciences and clinical applications of stem cell-based cell replacement therapies for neurodegenerative diseases.

Introduction

One of the most important issues in stem cell biology is to uncover molecular mechanisms underlying stem cell self-renewal. Self-renewal is essential for stem cells because it is required for all stem cells to perpetuate themselves. Neural stem cells are a subset of undifferentiated precursors that retain the ability to proliferate and self-renew, and have the capacity to give rise to both neuronal and glial lineages [1], [2], [3], [4]. Although the functional properties of neural stem cells have been studied extensively, we have just begun to understand how self-renewal of neural stem cells is regulated. A complete understanding of neural stem cells requires the identification of molecules that determine the self-renewal character of these cells. This review touches on some of the recently characterized pathways that are involved in regulating this process.

Section snippets

Transcription regulators

Batteries of transcription factors have been proposed to control neural stem cell self-renewal (Fig. 1). Orphan nuclear receptor TLX is an essential transcriptional regulator of neural stem cell maintenance and self-renewal in the adult brain [5]. Although TLX knockout mice are viable and appear normal at birth, the TLX gene has been shown to be required for the formation of superficial cortical layers and the zinc-containing cortical circuits in embryonic brains [6], [7], to regulate the

Epigenetic control

Stem cell self-renewal and differentiation are the result of transcription control in concert with chromatin remodeling and epigenetic modifications. During central nervous system development in vertebrates, neural stem cell fate are strictly controlled under regional and temporal manners [58], accompanied by precise epigenetic control, including covalent histone modification and DNA methylation of CpG dinucleotides.

Histone modification includes histone acetylation, methylation,

miRNA regulators

Many different classes of small non-coding RNAs are present in the brain, with diverse roles including RNA modification and chromatin remodeling [81]. Small double-stranded modulatory RNAs have been proposed to regulate the generation of neurons from adult neural stem cells by binding to REST [82]. miRNA is another recently identified large family of small non-coding RNAs, which are likely key post-transcriptional players in stem cell self-renewal and differentiation (Fig. 3). miRNAs are short

Cell-extrinsic signaling

Stem cell self-renewal and differentiation is also regulated by the specialized microenvironment, or niche, in which these cells reside [114], [115], [116], [117]. Direct physical interactions between stem cells and their niches are critical for maintaining stem cell characters. Signaling molecules in the niche are composed of soluble factors, membrane bound molecules and extracellular matrix, including Wnt, Notch and Sonic hedgehog (Shh) [114]. Receptor tyrosine kinase (RTK) signaling has also

Conclusion

An emerging regulatory network controlling stem cell self-renewal and differentiation is defined by integration of cell-intrinsic regulators, including transcription factors, epigenetic controls, and small RNA regulators, with cell-extrinsic signals from stem cell niches. These mechanisms are coordinated to regulate the development, maintenance, self-renewal and differentiation of stem cells. Unraveling how individual signaling cascades integrate into the global regulatory networks will be

Reviewers

Dr. Hongjun Song, Assistant Professor of Neurology, Institute for Cell Engineering, Departments of Neurology & Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.

Dr. Xinyu Zhao, Assistant Professor, Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States.

Acknowledgements

We apologize to colleagues whose work could not be cited due to space limitations and thank Rose Chavarin and Dr. Kamil Alzayady for proofreading of the manuscript. GS is a Herbert Horvitz Fellow and RS is a NIH NIMH DPN Fellow. YS is a Kimmel Scholar. This work is supported by Whitehall Foundation, the Margaret E. Early Medical Research Trust, the Sidney Kimmel Foundation, and NIH NINDS.

Dr. Yanhong Shi is an assistant professor of Neurosciences in Beckman Research Institute of City of Hope, Duarte, CA. Dr. Shi's research focuses specifically on neural stem cells in the adult brain. She is interested in characterizing the molecular cascades that program these cells to be self-renewable. Dr. Shi received her PhD degree from Northwestern University, Evanston, IL, followed by a postdoctoral training in the Salk Institute, La Jolla, CA, where she gained valuable experiences in the

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    Dr. Yanhong Shi is an assistant professor of Neurosciences in Beckman Research Institute of City of Hope, Duarte, CA. Dr. Shi's research focuses specifically on neural stem cells in the adult brain. She is interested in characterizing the molecular cascades that program these cells to be self-renewable. Dr. Shi received her PhD degree from Northwestern University, Evanston, IL, followed by a postdoctoral training in the Salk Institute, La Jolla, CA, where she gained valuable experiences in the gene expression laboratory and laboratory of Genetics under the guidance of Drs. Ronald M. Evans and Fred Gage. Dr. Shi is the recipient of a number of prestigious awards and has published her work extensively in respected scientific journals, including Nature, Genes and Development, and Proceedings of the National Academy of Sciences of the United States of America.

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