The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex.

Erin Knock,Andrew Dimond,Donna Leaford,João Pereira,Patrick D Lombard,Brian Hendrich,Frederick J Livesey

doi:10.1186/s13064-015-0040-z

Abstract

BackgroundChromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice.ResultsDeletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development.ConclusionsOur data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-015-0040-z) contains supplementary material, which is available to authorized users.

Highlights

Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis
Loss of methyl-CpG binding domain 3 (MBD3)/nucleosome remodeling and deacetylation (NuRD) function results in fewer cortical neurons MBD3 is expressed in cells of the ventricular zone (VZ) and sub-ventricular zone (SVZ) at E12.5 and from E14.5 is expressed in a sub-population of cortical plate neurons (Figure 1A)
While Cre-mediated excision of the floxed Mbd3 allele used in this study results in loss of MBD3A and MBD3B only, no anti-MBD3 reactivity was detectable in the brains of conditional knockouts (cKO) embryos after E12.5, indicating that MBD3C is not significantly expressed in the developing cortex

Summary

Introduction

Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Intermediate or basal progenitor cells are found in the sub-ventricular zone (SVZ) of the developing cortex. These progenitor cells are capable of symmetric division to produce two neurons and function to increase the neurogenic capacity of the apical progenitors [3]. A role for one MBD3/NuRD component protein, CHD4, in promoting synaptic connectivity in postnatal mouse brain has been described [21], but the function of MBD3/NuRD during neurogenesis has not been reported

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