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Nucleic Acids Res. 2019 Jan 10;47(1):168-183. doi: 10.1093/nar/gky953.

DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex.

Author information

Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Bioinformatics Group, Department of Computer Science, Albert-Ludwigs-University Freiburg, 79110 Freiburg, Germany.
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
DFG-Research Center and Cluster of Excellence for Regenerative Therapies (CRTD), School of Medicine, Technical University Dresden, 01307 Dresden, Germany.
Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Centre for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
Center for non-coding RNA in Technology and Health, University of Copenhagen, DK-1870 Frederiksberg C, Denmark.


Cortical development is controlled by transcriptional programs, which are orchestrated by transcription factors. Yet, stable inheritance of spatio-temporal activity of factors influencing cell fate and localization in different layers is only partly understood. Here we find that deletion of Dot1l in the murine telencephalon leads to cortical layering defects, indicating DOT1L activity and chromatin methylation at H3K79 impact on the cell cycle, and influence transcriptional programs conferring upper layer identity in early progenitors. Specifically, DOT1L prevents premature differentiation by increasing expression of genes that regulate asymmetric cell division (Vangl2, Cenpj). Loss of DOT1L results in reduced numbers of progenitors expressing genes including SoxB1 gene family members. Loss of DOT1L also leads to altered cortical distribution of deep layer neurons that express either TBR1, CTIP2 or SOX5, and less activation of transcriptional programs that are characteristic for upper layer neurons (Satb2, Pou3f3, Cux2, SoxC family members). Data from three different mouse models suggest that DOT1L balances transcriptional programs necessary for proper neuronal composition and distribution in the six cortical layers. Furthermore, because loss of DOT1L in the pre-neurogenic phase of development impairs specifically generation of SATB2-expressing upper layer neurons, our data suggest that DOT1L primes upper layer identity in cortical progenitors.

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