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Articles, Development/Plasticity/Repair

REST Regulates Non–Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II

Hyung Joon Kim, Ahmet M. Denli, Rebecca Wright, Tithi D. Baul, Gregory D. Clemenson, Ari S. Morcos, Chunmei Zhao, Simon T. Schafer, Fred H. Gage and Mohamedi N. Kagalwala
Journal of Neuroscience 4 November 2015, 35 (44) 14872-14884; https://doi.org/10.1523/JNEUROSCI.4286-14.2015
Hyung Joon Kim
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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  • ORCID record for Hyung Joon Kim
Ahmet M. Denli
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Rebecca Wright
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Tithi D. Baul
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Gregory D. Clemenson
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Ari S. Morcos
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
2Program in Neuroscience, Harvard University, Boston, Massachusetts 02138
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Chunmei Zhao
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Simon T. Schafer
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Fred H. Gage
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Mohamedi N. Kagalwala
1Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and
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Abstract

RE-1 silencing transcription factor (REST), a master negative regulator of neuronal differentiation, controls neurogenesis by preventing the differentiation of neural stem cells. Here we focused on the role of REST in the early steps of differentiation and maturation of adult hippocampal progenitors (AHPs). REST knockdown promoted differentiation and affected the maturation of rat AHPs. Surprisingly, REST knockdown cells enhanced the differentiation of neighboring wild-type AHPs, suggesting that REST may play a non–cell-autonomous role. Gene expression analysis identified Secretogranin II (Scg2) as the major secreted REST target responsible for the non–cell-autonomous phenotype. Loss-of-function of Scg2 inhibited differentiation in vitro, and exogenous SCG2 partially rescued this phenotype. Knockdown of REST in neural progenitors in mice led to precocious maturation into neurons at the expense of mushroom spines in vivo. In summary, we found that, in addition to its cell-autonomous function, REST regulates differentiation and maturation of AHPs non–cell-autonomously via SCG2.

SIGNIFICANCE STATEMENT Our results reveal that REST regulates differentiation and maturation of neural progenitor cells in vitro by orchestrating both cell-intrinsic and non–cell-autonomous factors and that Scg2 is a major secretory target of REST with a differentiation-enhancing activity in a paracrine manner. In vivo, REST depletion causes accelerated differentiation of newborn neurons at the expense of spine defects, suggesting a potential role for REST in the timing of the maturation of granule neurons.

  • adult neurogenesis
  • microfludics
  • neurosecretory
  • REST/NRSF
  • SCG2
  • stem cells
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The Journal of Neuroscience: 35 (44)
Journal of Neuroscience
Vol. 35, Issue 44
4 Nov 2015
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REST Regulates Non–Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II
Hyung Joon Kim, Ahmet M. Denli, Rebecca Wright, Tithi D. Baul, Gregory D. Clemenson, Ari S. Morcos, Chunmei Zhao, Simon T. Schafer, Fred H. Gage, Mohamedi N. Kagalwala
Journal of Neuroscience 4 November 2015, 35 (44) 14872-14884; DOI: 10.1523/JNEUROSCI.4286-14.2015

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REST Regulates Non–Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II
Hyung Joon Kim, Ahmet M. Denli, Rebecca Wright, Tithi D. Baul, Gregory D. Clemenson, Ari S. Morcos, Chunmei Zhao, Simon T. Schafer, Fred H. Gage, Mohamedi N. Kagalwala
Journal of Neuroscience 4 November 2015, 35 (44) 14872-14884; DOI: 10.1523/JNEUROSCI.4286-14.2015
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Keywords

  • adult neurogenesis
  • microfludics
  • neurosecretory
  • Rest/Nrsf
  • SCG2
  • stem cells

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