The methyl-CpG binding proteins Mecp2, Mbd2 and Kaiso are dispensable for mouse embryogenesis, but play a redundant function in neural differentiation.
BACKGROUND
The precise molecular changes that occur when a neural stem (NS) cell switches from a programme of self-renewal to commit towards a specific lineage are not currently well understood. However it is clear that control of gene expression plays an important role in this process. DNA methylation, a mark of transcriptionally silent chromatin, has similarly been shown to play important roles in neural cell fate commitment in vivo. While DNA methylation is known to play important roles in neural specification during embryonic development, no such role has been shown for any of the methyl-CpG binding proteins (Mecps) in mice.


RESULTS
To explore the role of DNA methylation in neural cell fate decisions, we have investigated the function of Mecps in mouse development and in neural stem cell derivation, maintenance, and differentiation. In order to test whether the absence of phenotype in singly-mutant animals could be due to functional redundancy between Mecps, we created mice and neural stem cells simultaneously lacking Mecp2, Mbd2 and Zbtb33. No evidence for functional redundancy between these genes in embryonic development or in the derivation or maintenance of neural stem cells in culture was detectable. However evidence for a defect in neuronal commitment of triple knockout NS cells was found.


CONCLUSIONS
Although DNA methylation is indispensable for mammalian embryonic development, we show that simultaneous deficiency of three methyl-CpG binding proteins genes is compatible with apparently normal mouse embryogenesis. Nevertheless, we provide genetic evidence for redundancy of function between methyl-CpG binding proteins in postnatal mice.
Martín Caballero
Isabel
I
Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Hansen
Janne
J
Leaford
Donna
D
Pollard
Steven
S
Hendrich
Brian D
BD
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D047108:Embryonic Development; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; C489326:Mbd2 protein, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D014157:Transcription Factors; C118822:Zbtb33 protein, mouse