Epigenetic regulation of neuronal dendrite and dendritic spine development

Abstract

Dendrites and the dendritic spines of neurons play key roles in the connectivity of the brain and have been recognized as the locus of long-term synaptic plasticity, which is correlated with learning and memory. The development of dendrites and spines in the mammalian central nervous system is a complex process that requires specific molecular events over a period of time. It has been shown that specific molecules are needed not only at the spine's point of contact, but also at a distance, providing signals that initiate a cascade of events leading to synapse formation. The specific molecules that act to signal neuronal differentiation, dendritic morphology, and synaptogenesis are tightly regulated by genetic and epigenetic programs. It has been shown that the dendritic spine structure and distribution are altered in many diseases, including many forms of mental retardation (MR), and can also be potentiated by neuronal activities and an enriched environment. Because dendritic spine pathologies are found in many types of MR, it has been proposed that an inability to form normal spines leads to the cognitive and motor deficits that are characteristic of MR. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and the noncoding RNA-mediated process, have profound regulatory roles in mammalian gene expression. The study of epigenetics focuses on cellular effects that result in a heritable pattern of gene expression without changes to genomic encoding. Despite extensive efforts to understand the molecular regulation of dendrite and spine development, epigenetic mechanisms have only recently been considered. In this review, we will focus on epigenetic mechanisms that regulate the development and maturation of dendrites and spines. We will discuss how epigenetic alterations could result in spine abnormalities that lead to MR, such as is seen in fragile X and Rett syndromes. We will also discuss both general methodology and recent technological advances in the study of neuronal dendrites and spines.

Keywords: dendritic spine; epigenetics; mental retardation; methyl-CpG binding protein 2 (MeCP2); microRNA; neurodevelopment; synapse.

Fig. 1. Schematic diagram of a mature neuron and synapse

A: A mature neuron has elaborate processes that are composed of multiple dendrites and one axon. Dendrites contain a large number of dendritic spines that form contacts, or synapses, with other neurons. The synapses are typically found on the dendritic shaft, located on stubby spines and filipodia. B: A neuronal synapse is the point of contact between two neurons, a presynaptic neuron and a postsynaptic neuron. It is characterized by specific synaptic proteins located on the pre- and postsynaptic sites.

Fig. 2. Common dendritic spine types in the CNS

Three types of dendritic spines are commonly found in the CNS. A: the long and thin filipodia spine with no head enlargement; B: the mushroom-like spine with a bulbous head attached to the dendrite by a narrow neck; and C: the short and stubby spine with no neck. It is believed that long, thin spines are mostly immature spines, and they develop into the more mature mushroom-like spines. CNS: central nervous system.

Fig. 3. The stages of morphological development of dendrites and dendritic spines

A: Immature neurons have shorter dendrites, and these dendrites have no spines. B: During synaptogenesis and neuronal maturation, neurons develop a more complex dendritic arbor, and these dendrites begin to form spines. Some of these spines start to receive input from the axons of other neurons. C: Mature neurons have elaborate dendritic trees and a high density of mature spines. These neurons form functional connections with other neurons and participate in the brain circuitry.

Fig. 4. Pathological changes in spine density. Common pathological alterations in dendritic spines are altered spine density and abnormal spine shapes

A: Healthy neuronal dendrites contain spines with a typical variation of spine types. B: Reduced spine density is common in many cognitive and developmental disorders, such as Rett syndrome. C: Increased spine density with abnormally increased long and thin types of spines is commonly found in patients with fragile X syndrome.

Fig. 5. Epigenetic regulation of biogenesis and functions of miRNA in the neuron

Transcription of miRNA, which can be regulated by epigenetic machinery, leads to the production of miRNA transcripts (pri-miRNAs), which are cleaved in the nucleus and exported into the cytoplasm as pre-miRNAs. The pre-miRNA is processed by the RNase Dicer and is likely associated with other accessory proteins, such as fragile X mental retardation protein (FMRP), to form an intermediate miRNA duplex. The leading strand of the miRNA duplex can then associate with the miRNA-induced silencing complex (miRISC), and then pair with sequences located on the 3′UTR of target mRNAs. This leads to translational repression of the target mRNA. Recent evidence suggests that RNA-binding proteins like FMRP interact with miRNAs to modulate mRNA translation. This example illustrates the effect of miRNA-mediated translational repression of proteins important for dendritic spine function.