Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells

New neurons It is now accepted that the adult brain has the plasticity to grow new cells, but the molecular mechanisms that maintain neurogenesis throughout life in certain brain regions are not known. One major influence on gene expression the structure of chromatin — the complex of nucleotides and protein that make up chromosomes. Lim et al . now show that in the postnatal mouse brain, the chromatin remodelling factor gene Mll1 ( mixed lineage leukaemia 1 ) prompts neural stem cells to form neurons, whereas in the absence of Mll1 the same stem cells produce glial cells, the non-neuronal cells that play a primarily supportive role the nervous system. Mll1 operates in part by activating the downstream gene Dlx2 , a key regulator of neurogenesis in the subventricular zone of the brain. Trithorax group (trxG) and Polycomb group (PcG) gene products are part of a chromatin remodelling system that activates or silences gene expression, respectively. This paper shows that show that Mll1 ( mixed-lineage leukemia 1 ), a trxG member, is required for neurogenesis in the postnatal brain. They show that, in Mll1 -deficient cells, expression of proneural and gliogenic regulatory genes are preserved, but Dlx2 , a key downstream regulator of subventricular zone neurogenesis, is not expressed. Epigenetic mechanisms that maintain neurogenesis throughout adult life remain poorly understood 1 . Trithorax group (trxG) and Polycomb group (PcG) gene products are part of an evolutionarily conserved chromatin remodelling system that activate or silence gene expression, respectively 2 . Although PcG member Bmi1 has been shown to be required for postnatal neural stem cell self-renewal 3 , 4 , the role of trxG genes remains unknown. Here we show that the trxG member Mll1 ( mixed-lineage leukaemia 1 ) is required for neurogenesis in the mouse postnatal brain. Mll1 -deficient subventricular zone neural stem cells survive, proliferate and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1 -deficient cells, early proneural Mash1 (also known as Ascl1 ) and gliogenic Olig2 expression are preserved, but Dlx2 , a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2 can rescue neurogenesis in Mll1 -deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2 is a direct target of MLL in subventricular zone cells. In differentiating wild-type subventricular zone cells, Mash1