From neural development to cognition: unexpected roles for chromatin

Abstract

Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have uncovered mutations in many chromatin regulators. These human genetic studies, along with studies in model organisms, are providing insight into chromatin regulatory mechanisms in neural development and how alterations to these mechanisms can cause cognitive deficits, such as intellectual disability. We discuss several implicated chromatin regulators, including BAF (also known as SWI/SNF) and CHD8 chromatin remodellers, HDAC4 and the Polycomb component EZH2. Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains. We speculate on the contribution of these similar mutations to disparate disorders.

Figure 1. Chromatin regulators have essential roles throughout neural development

The fundamental processes of neural development are illustrated. Chromatin regulators discussed in this Review are noted under the processes in which they have important roles. The key indicates whether a particular regulator promotes or inhibits each neurodevelopmental process. a | A timeline of human neural development. b | The development of the vertebrate nervous system begins during gastrulation. In the early embryo, neural progenitor cells undergo symmetrical proliferative division. c | With the expansion of the number of cell types and the size of the nervous system, the cell bodies of both neural progenitors and resulting postmitotic neurons migrate away from their birthplace to appropriate regions in response to environmental cues. d | Neural progenitors asymmetrically divide to give rise to neurons, glial cells or intermediate progenitors. Neural differentiation generates enormous numbers of diverse cell types in the nervous system. e | After migrating neurons have reached their destinations, they extend axonal and dendritic processes, which are guided by intricate cellular interactions and guidance molecules to appropriate target regions, where they further elaborate processes to cover receptive fields and innervate targets. f | Mature synapses are formed between neurons that are connected to each other. Synaptogenesis begins during embryonic development, but subsequent synaptic stabilization and plasticity occur throughout life and are adaptive to learning experiences and other activity-dependent environmental inputs. g | Active apoptosis and local degenerative pruning events maintain and refine established neuronal morphologies and neural circuit assembly. NPC, neural progenitor cell. Part a is modified, with permission, from REF. © American Psychiatric Association.

Figure 2. BAF complex roles in neurodevelopment and disorders of brain function

a | The composition of neural progenitor BAF (npBAF) and neuronal BAF (nBAF) complexes is indicated, along with the triple-negative genetic circuit that leads to npBAF to nBAF switching and their involvement in various disorders (right). b | Knockout (−/−) of BRG and knockdown (kd) of npBAF subunits BAF45A and BAF53A in neural progenitors (green cells) impede neural progenitor self-renewal and differentiation into postmitotic neurons (blue cells). Loss-of-function of BRG and BAF57 in the developing nervous system and nBAF subunits BAF45B and BAF53B affects activity-dependent process outgrowth of postmitotic neurons. MicroRNA (miRNA)-mediated direct conversion of human fibroblasts to neurons recapitulates the switching of npBAF to nBAF complexes during normal neural development. miR-9, miR-9* and miR-124 act together by binding to independent sites in the BAF53A 3′ untranslated regions, functioning as a molecular AND gate for this developmental transition. c | Bap55, the homologue of mammalian BAF53A and BAF52B in Drosophila melanogaster, controls dendritic targeting of olfactory projection neurons (PNs; red). In comparison to wild-type PNs, which target glomerulus Dl1 (green, left), PNs lacking Bap55 are precisely mistargeted to an alternative glomerulus, Da4l (green, right), in the antennal lobe. This dendritic targeting occurs before the axonal patterning of the glomerulus and is thus thought to be mediated through genetic, cell-intrinsic mechanisms and not in response to particular guidance molecules. shRNA, short hairpin RNA.

Figure 3. Repressive chromatin modifiers involved in disorders of brain function

a | During later stages of neurogenesis, enhancer of zeste 2 (EZH2) has been shown to repress particular β-catenin target genes in neural progenitors in order to mediate proper cell fate transitions. It is also likely that EZH2 and BAF complexes have antagonistic roles in these cells as they do in embryonic stem cells and Drosophila melanogaster. Decreased functional EZH2 dosage (owing to haploinsufficiency or altered function of mutant proteins) will lead to de-repression or over-expression of its targets, leading to altered developmental pathways. Patients with Weaver’s syndrome have macrocephaly and learning disabilities of varying severity. b | In normal development, histone deacetylase 4 (HDAC4) is dynamically regulated in the cell, moving into and out of the nucleus in response to physiological signals. When localized in the nucleus, HDAC4 binds myocyte-specific enhancer factor 2 (MEF2) transcription factors and recruits repressors such as class I HDACs and heterochromatin protein 1 (HP1) to MEF2 targets. HDAC4 dosage or nuclear residence is critically affected in patients with brachydactyly mental retardation (BDMR) syndrome, probably leading to misregulated MEF2 target gene expression in particular temporal and cellular contexts. H3K27me3, histone H3 trimethylated at lysine 27; PRC2, Polycomb repressive complex 2.