Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2.
Methyl-CpG-binding protein 2 (MeCP2), a methyl-CpG-binding domain protein family member which is expressed predominantly in neurons in the nervous system, acts as a transcriptional repressor by binding to methylated genes, and mutations in mecp2 cause the neurological disorder known as Rett syndrome (RTT). Although MeCP2 has been reported to regulate neuronal maturation rather than fate specification of neural precursor cells (NPCs), we have previously shown that it inhibits astrocyte differentiation of NPCs when ectopically expressed. Here, we show that expression of MeCP2 in NPCs not only suppresses astrocytic differentiation but actually promotes neuronal differentiation, even in the presence of well-known astrocyte-inducing cytokines. This dual function of MeCP2 was abolished by the MEK inhibitor U0126. Moreover, we observed that a truncated form of MeCP2 found in RTT patients fails to promote neuronal differentiation. We further demonstrate that transplanted MeCP2-expressing NPCs differentiate in vivo into neurons in two non-neurogenic regions, striatum and spinal cord. These results suggest a possible therapeutic application for MeCP2 in neurodegenerative diseases and injuries to the central nervous system.
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0101, Japan.
Keita
K
Tsujimura
Masahiko
M
Abematsu
Jun
J
Kohyama
Masakazu
M
Namihira
Kinichi
K
Nakashima
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009416:Nerve Regeneration / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D004791:Enzyme Inhibitors; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D048369:MAP Kinase Kinase 1