Emerging roles for MEF2 in brain development and mental disorders

Abstract

The MEF2 family of transcription factors regulate large programs of gene expression important for the development and maintenance of many tissues, including the brain. MEF2 proteins are regulated by neuronal synaptic activity, and they recruit several epigenetic enzymes to influence chromatin structure and gene expression during development and throughout adulthood. Here, we provide a brief review of the recent literature reporting important roles for MEF2 during early brain development and function, and we highlight emerging roles for MEF2 as a risk factor for multiple neurodevelopmental disorders and mental illnesses, such as autism, intellectual disability, and schizophrenia.

Figure 1.. MEF2 expression in the mouse brain.

The four MEF2 proteins (A-D) are differentially expressed in unique but overlapping regions in the postnatal and adult mouse brain [–14], suggesting that these proteins may have specific functions in different areas. Heatmap denotes relative expression.

Figure 2.. Transcriptional variants and post-translational modifications of MEF2C.

(A) Mef2c mRNA splicing. Mef2 transcripts undergo tissue-specific alternative mRNA splicing at different sites [, –20]. All transcripts will contain either the α1 or α2 (exon 3) domain, and ~50% of the transcripts will also contain the γ domain (located within exon 9). The mouse brain MEF2C protein possesses the α1 and β domains, while mouse muscle/heart tissues contain MEF2C variants that include α1 or α2, but they exclude β (Sciabica et al 2016, SCIEX). (B) Domains and post-translational modifications of MEF2C. The MADS and MEF2 domains mediate MEF2 dimerization and DNA binding as well as co-factor recruitment, and the TAD recruits co-factors to regulate transcription activity (TA). Multiple forms of posttranslational modifications occur on MEF2C, including phosphorylation, acetylation and sumoylation, that regulate its activity, stability or DNA binding affinity [–42]. Modifications in green increase TA, in red decrease TA, and in black induce protein degradation. NLS: Nuclear Localization Signal. P: Phosphorylation. Su: Sumoylation. Ac: Acetylation. S-Ni: S-Nitrosylation. TAD: Transactivation Domain.

Figure 3.. Model for MEF2 regulation and function in neurons.

Sensory experiences lead to neuronal depolarization that results in an increase in intracellular calcium and subsequent changes in MEF2 transcriptional activity by altering posttranslational modifications on MEF2 and affecting co-factor interactions. MEF2s bind to DNA as homo- or heterodimers and can either activate or repress specific target genes that have numerous downstream functions, including synaptic connectivity regulation. The RNA-binding protein, FMRP, transports a subset of the MEF2-regulated mRNAs into dendrites. FMRP can control local protein synthesis of common MEF2-FMRP target mRNAs to regulate synapse elimination. Neurodevelopmental disorders associated with MEF2 are labeled in red.