The Transcriptional Coactivator Querkopf Controls Adult Neurogenesis

Abstract

The adult mammalian brain maintains populations of neural stem cells within discrete proliferative zones. Understanding of the molecular mechanisms regulating adult neural stem cell function is limited. Here, we show that MYST family histone acetyltransferase Querkopf (Qkf, Myst4, Morf)-deficient mice have cumulative defects in adult neurogenesis in vivo, resulting in declining numbers of olfactory bulb interneurons, a population of neurons produced in large numbers during adulthood. Qkf-deficient mice have fewer neural stem cells and fewer migrating neuroblasts in the rostral migratory stream. Qkf gene expression is strong in the neurogenic subventricular zone. A population enriched in multipotent cells can be isolated from this region on the basis of Qkf gene expression. Neural stem cells/progenitor cells isolated from Qkf mutant mice exhibited a reduced self-renewal capacity and a reduced ability to produce differentiated neurons. Together, our data show that Qkf is essential for normal adult neurogenesis.

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…Although MOZ regulates hematopoiesis and proliferation of related progenitor cells (Katsumoto et al, 2006;Thomas et al, 2006), MORF has a key role in the neural stem cell compartment (Merson et al, 2006), raising an interesting possibility as to whether MOZ and MORF play a role in other stem cells during normal development (Figure 4a). The leukemic fusion protein MOZ-TIF2 has been shown to promote self-renewal of leukemic stem cells (Huntly et al, 2004), so one question is whether other leukemia-derived MOZ and MORF proteins have a similar role (Figure 4b).…”

“…With a residual MORF mRNA level of B10%, homozygous mice are small in size and display craniofacial abnormalities and severe defects in cerebral cortex development, suggesting that MORF is important for neurogenesis. Neural progenitor cells from these mice exhibit defects in self-renewal and differentiation (Merson et al, 2006). Related to this, Enok is required for mushroom body formation in fly brain (Scott et al, 2001).…”

Epigenetic regulation of aging stem cells

“…The role of MOZ in adult HSCs has not yet been determined due to embryonic lethality of Moz-deficient mouse mutants, but MOZ is likely to play a similar role in adult HSC self-renewal. In NSCs, MYST4/ QUERKOPF has a role in regulating neurogenic potential and proliferation during development and in the adult SVZ (Thomas et al, 2000;Rietze et al, 2001;Merson et al, 2006). Mice with a hypomorphic Querkopf allele show modestly reduced numbers of long-term label retaining cells in the adult SVZ, reduced proliferation of neurospheres in culture and impaired neuronal differentiation in vitro and in vivo leading to reduced numbers of olfactory interneurons in adults (Thomas et al, 2000;Rietze et al, 2001;Merson et al, 2006).…”

“…In NSCs, MYST4/ QUERKOPF has a role in regulating neurogenic potential and proliferation during development and in the adult SVZ (Thomas et al, 2000;Rietze et al, 2001;Merson et al, 2006). Mice with a hypomorphic Querkopf allele show modestly reduced numbers of long-term label retaining cells in the adult SVZ, reduced proliferation of neurospheres in culture and impaired neuronal differentiation in vitro and in vivo leading to reduced numbers of olfactory interneurons in adults (Thomas et al, 2000;Rietze et al, 2001;Merson et al, 2006). It will be informative to investigate the role of MYST4/QUERKOPF in controlling histone and protein acetylation in NSCs and to further explore if MYST4/QUERKOPF expression or targeting changes during aging.…”

Distinct Modes of Neuron Addition in Adult Mouse Neurogenesis

“…Whereas some studies suggested that most cells that survived initial 4 weeks could still be detected after several months (Kempermann et al, 2003;Lemasson et al, 2005), others reported a further decrease in the number of labeled neurons during 365 d of survival (Petreanu and Alvarez-Buylla, 2002;Kohwi et al, 2007). Extrapolating these data from labeling a single or few cohorts would suggest a considerable contribution of adultgenerated neurons to the OB network, leading several studies to propose an increase in the size of the dentate gyrus (DG) and the OB attributable to adult neurogenesis (Kempermann et al, 2003;Merson et al, 2006). Although the majority of the BrdU analysis focused on the GCL, in vivo imaging could only access the GL where a turnover of only 3% of the neurons was observed (Mizrahi et al, 2006).…”