PMID- 22848609
OWN - NLM
STAT- MEDLINE
DCOM- 20130409
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 7
DP  - 2012
TI  - Elevated IKKalpha accelerates the differentiation of human neuronal progenitor cells 
      and induces MeCP2-dependent BDNF expression.
PG  - e41794
LID - 10.1371/journal.pone.0041794 [doi]
LID - e41794
AB  - The IkappaB kinase alpha (IKKalpha) is implicated in the differentiation of epithelial and 
      immune cells. We examined whether IKKalpha also plays a role in the differentiation 
      and maturation of embryonic human neuronal progenitor cells (NPCs). We find that 
      expression of an extra copy of IKKalpha (IKKalpha+) blocks self-renewal and accelerates 
      the differentiation of NPCs. This coincides with reduced expression of the 
      Repressor Element Silencing Transcription Factor/Neuron-Restrictive Silencing 
      Factor (REST/NRSF), which is a prominent inhibitor of neurogenesis, and 
      subsequent induction of the pro-differentiation non-coding RNA, miR-124a. 
      However, the effects of IKKalpha on REST/NRSF and miR-124a expression are likely to 
      be indirect. IKKalpha+ neurons display extensive neurite outgrowth and accumulate 
      protein markers of neuronal maturation such as SCG10/stathmin-2, postsynaptic 
      density 95 (PSD95), syntaxin, and methyl-CpG binding protein 2 (MeCP2). 
      Interestingly, IKKalpha associates with MeCP2 in the nuclei of human neurons and can 
      phosphorylate MeCP2 in vitro. Using chromatin immunoprecipitation assays, we find 
      that IKKalpha is recruited to the exon-IV brain-derived neurotrophic factor (BDNF) 
      promoter, which is a well-characterized target of MeCP2 activity. Moreover, IKKalpha 
      induces the transcription of BDNF and knockdown expression of MeCP2 interferes 
      with this event. These studies highlight a role for IKKalpha in accelerating the 
      differentiation of human NPCs and identify IKKalpha as a potential regulator of MeCP2 
      function and BDNF expression.
FAU - Khoshnan, Ali
AU  - Khoshnan A
AD  - Biology Division 216-76, California Institute of Technology, Pasadena, 
      California, United States of America. khoshnan@caltech.edu
FAU - Patterson, Paul H
AU  - Patterson PH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120727
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (MIRN124 microRNA, human)
RN  - 0 (Methyl-CpG-Binding Protein 2)
RN  - 0 (MicroRNAs)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (Repressor Proteins)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics
MH  - *Cell Differentiation
MH  - Cell Line
MH  - Cell Proliferation
MH  - *Gene Expression Regulation
MH  - Humans
MH  - I-kappa B Kinase/*metabolism
MH  - Methyl-CpG-Binding Protein 2/*metabolism
MH  - MicroRNAs/genetics/metabolism
MH  - Neural Stem Cells/*cytology/enzymology/metabolism
MH  - Neurons/*cytology
MH  - Rats
MH  - Repressor Proteins/metabolism
MH  - Time Factors
PMC - PMC3407048
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/08/01 06:00
MHDA- 2013/04/10 06:00
PMCR- 2012/07/27
CRDT- 2012/08/01 06:00
PHST- 2012/03/22 00:00 [received]
PHST- 2012/06/25 00:00 [accepted]
PHST- 2012/08/01 06:00 [entrez]
PHST- 2012/08/01 06:00 [pubmed]
PHST- 2013/04/10 06:00 [medline]
PHST- 2012/07/27 00:00 [pmc-release]
AID - PONE-D-12-08418 [pii]
AID - 10.1371/journal.pone.0041794 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(7):e41794. doi: 10.1371/journal.pone.0041794. Epub 2012 Jul 27.