神経分化とLINE挿入

Fred H. Gageという研究者のことは知らなかったが、LINEの研究では最近ずいぶん活躍しているようである。

ここ数年の研究で神経幹細胞から神経が分化していく際に、（１）ゲノム改変が起こっているようであり、その機序として（２）LINE　エレメントの新たな転移機構を提唱しているが、その際（３）methyl-CpG-binding protein 2 (MeCP2)が欠失しているとLINEの活躍は激しくなることを今回示した。

1. Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, Morell M, O'Shea KS, Moran JV, Gage FH: L1 retrotransposition in human neural progenitor cells. Nature 460(7259):1127-1131, 2009
   
   
2. Alisch RS, Garcia-Perez JL, Muotri AR, Gage FH, Moran JV: Unconventional translation of mammalian LINE-1 retrotransposons. Genes & development 20(2):210-224, 2006
   
   
3. Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH: Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435(7044):903-910, 2005

Kazazian教授のあとを継ぐのはこの研究者のラインなのか？？注目しておこう。

L1 retrotransposition in neurons is modulated by MeCP2

Alysson R. Muotri, Maria C. N. Marchetto, Nicole G. Coufal, Ruth Oefner, Gene Yeo, Kinichi Nakashima & Fred H. Gage

Nature
Volume:468
Pages:443–44
Date published:(18 November 2010)

Received　27 April 2010
Accepted　30 September 2010
Online 　17 November 2010

Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes^{1, 2, 3}. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning^{4, 5, 6}. We have shown previously that L1 retrotransposons are capable of mobilization in neuronal progenitor cells from rodents and humans and evidence of massive L1 insertions was observed in adult brain tissues but not in other somatic tissues^{7, 8}. In addition, L1 mobility in the adult hippocampus can be influenced by the environment⁹. The neuronal specificity of somatic L1 retrotransposition in neural progenitors is partially due to the transition of a Sox2/HDAC1 repressor complex to a Wnt-mediated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activator^{7, 10}. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription⁷. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism^{11, 12}. Further understanding of the molecular mechanisms that regulate L1 expression should provide new insights into the role of L1 retrotransposition during brain development. Here we show that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that patients with Rett syndrome (RTT), carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. Our findings add a new level of complexity to the molecular events that can lead to neurological disorders.