MRG15, a component of HAT and HDAC complexes, is essential for proliferation and differentiation of neural precursor cells

Abstract

Neurogenesis during development depends on the coordinated regulation of self-renewal and differentiation of neural precursor cells. Chromatin regulation is a key step in self-renewal activity and fate decision of neural precursor cells. However, the molecular mechanism(s) of this regulation is not fully understood. Here, we demonstrate for the first time that MRG15, a chromatin regulator, is important for proliferation and neural fate decision of neural precursor cells. Neuroepithelia from Mrg15 deficient embryonic brain are much thinner than those from control, and apoptotic cells increase in this region. We isolated neural precursor cells from Mrg15 deficient and wild-type embryonic whole brains and produced neurospheres to measure the self-renewal and differentiation abilities of these cells in vitro. Neurospheres culture from Mrg15 deficient embryo grew less-efficiently than those from wild-type. Measurement of proliferation, using BrdU incorporation, revealed that Mrg15 deficient neural precursor cells have reduced proliferation ability and apoptotic cells do not increase during in vitro culture. The reduced proliferation of Mrg15 deficient neural precursor cells most likely accounts for the thinner neuroepithelia in Mrg15 deficient embryonic brain. Moreover, we also demonstrate Mrg15 deficient neural precursor cells are defective in differentiation into neurons in vitro. Our results demonstrate that MRG15 has more than one function in neurogenesis and defines a novel role for this chromatin regulator that integrates proliferation and cell-fate determination in neurogenesis during development.

Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in theC. elegansgerm line

“…Here we describe the role of the proteasome in regulating the accumulation of MRG-1, a protein implicated in promoting the proliferative fate in various systems (Chen et al, 2009;Tominaga et al, 2005;Zhang et al, 2010). We found that reducing proteasome activity, or mutating the putative E3 ligase RFP-1, elevated the levels of MRG-1 and enhanced stem cell overproliferation.…”

“…MRG-1 is necessary for proliferation of the primordial germ cells, with mutants lacking both maternal and zygotic activity completely lacking a germ line due to failure of the primordial germ cells to proliferate (Fujita et al, 2002). Additionally, the murine homologue of MRG-1, MRG15, promotes proliferation of neural precursor cells (Chen et al, 2009). Therefore, MRG-1 is a good candidate for a proliferative fate-promoting protein, the accumulation of which may be controlled through proteasomal degradation.…”

“…MRG-1 contains a chromodomain and has homologues from yeast to humans (Bertram et al, 1999;Gorman et al, 1995;Nakayama et al, 2003;Reid et al, 2004). It associates with chromatin (Takasaki et al, 2007), and MRG15, the mammalian homologue, complexes with proteins involved in acetylation (Akhtar and Becker, 2000;Cai et al, 2003;Chen et al, 2009;Doyon et al, 2004;Eisen et al, 2001;Hayakawa et al, 2007;Ikura et al, 2000;Joshi and Struhl, 2005;Pardo et al, 2002;Yochum and Ayer, 2002); as such, MRG-1 is likely to be involved in controlling the expression of many genes. The mammalian homologue associates with both acetyltransferases and deacetylases.…”

“…Therefore, MRG-1 could both promote the expression of proteins necessary for proliferation and repress the expression of proteins necessary for differentiation. Its influence on stem cell proliferation might be conserved, as lack of MRG15, the MRG-1 homologue in mammals, results in smaller and fewer murine neurospheres (Chen et al, 2009). …”

“…MRG-1 has multiple functions in C. elegans, including facilitating synaptonemal complex-independent pairing of homologous chromosomes (Dombecki et al, 2011), maintaining genomic integrity in germ cells (Xu et al, 2012) and repressing the expression of X-linked genes in the germ line (Takasaki et al, 2007). Additionally, MRG-1 is necessary for proliferation of C. elegans primordial germ cells (Fujita et al, 2002;Takasaki et al, 2007), and loss of MRG15 reduces the proliferation capacity of neural precursor cells in mice (Chen et al, 2009). We demonstrate that MRG-1 also contributes to the proliferation capacity of stem cells in adult Fig.…”