MYST family histone acetyltransferases in nervous system development and neural stem cells
Acetylation of lysine residues in histone amino-terminal tails is a hallmark of transcriptionally active gene loci in mammals. Histone acetylation is performed by histone acetyltransferases and thought to keep the chromatin in an open configuration (Figure 1A). The MYST family, characterised by its MYST histone acetyltransferase domain, has five members (Figure 1B). Our findings show that two of its members, Querkopf (Qkf, Morf, Myst4, Kat6b) and Monocytic leukaemia zinc finger protein (Moz, Myst3, Kat6a) are proteins that regulate stem cell dynamics at the transcriptional level.
Figure 1: Histone acetyltransferases acetylate lysine residues in the amino-terminal tails of histones, thereby rendering the chromatin accessible for transcriptional activation modelled in (A). The MYST histone acetyltransferase family consists of 5 members in mammals (B) characterised by their MYST domain.
The Qkf gene is initially expressed at low levels throughout the early embryo, but at E10.5 of development a strong domain of expression emerges in the dorsal telencephalon, the earliest cerebral cortex primordium. High levels of expression are maintained in this region throughout cortical development, both in the proliferating ventricular zone cells (the ‘stem cells’ of the cortex) and in the differentiating neuroblasts that migrate away from the ventricular zone to form the cortical plate (Figure 2).
The cortical plate is where further maturation of the newly born neurons takes place to ultimately form the adult six-layered cortex. Qkf has a dynamic pattern of expression and during the latter stages of development strong domains of expression also arise in the ventral telencephalon, which forms the caudate-putamen, and in the olfactory bulbs.
Figure 2: Expression of a lacZ reporter gene in the Qkf locus shows strong Qkf gene activity in the dorsal telencephalon at embryonic day 12.5 (dTel, blue, A) and RNA/RNA in situ hybridisation documents continuous strong expression of the endogenous Qkf gene in the ventricular germinal zone and the cerebral cortex primordium, the cortical plate at embryonic day 15.5 (Ctx, B). BrdU labelling of cells in DNA synthesis phase (brown, C) shows that Qkf deficient ventricular germinal zone cells (mt, VZ in C) proliferate less than controls (wt in C). Moreover, the Qkf deficient ventricular germinal zone gives rise to fewer differentiating neurons, which is manifest in the smaller cortical plate (CP in C).
We generated a Qkf deficient mouse strain. Mice deficient in the expression of Qkf have a reduction in the number of proliferating cells in the ventricular zone and reduced numbers of newly born neurons in the cortical plate at all stages of cortical neurogenesis (Figure 2). This suggests that Qkf is involved in the balance between proliferation and differentiation. As a result of these developmental defects the adult Qkf deficient mice have a reduction in the size of the cerebral cortex. In addition, Qkf deficient mice have reduced numbers of interneurons, cells that migrate into the cortex from the ventral telencephalon.
Adult mice lacking Qkf have a reduction in the number of neural stem cells in the forebrain, a stem cell population that continually gives rise to new neurons throughout life. Consequently, adult Qkf deficient mice fail to generate normal numbers of new neurons during adulthood (Figure 3).
Interestingly, while examining a mouse strain deficient in Moz, we found that Moz deficient mice lack long-term reconstituting haematopoietic stem cells. Therefore the closely related proteins Qkf and Moz perform essential corresponding roles in diverse stem cell populations.
