Functional conservation of MBD proteins: MeCP2 and Drosophila MBD proteins alter sleep

Abstract

Proteins containing a methyl-CpG-binding domain (MBD) bind 5mC and convert the methylation pattern information into appropriate functional cellular states. The correct readout of epigenetic marks is of particular importance in the nervous system where abnormal expression or compromised MBD protein function, can lead to disease and developmental disorders. Recent evidence indicates the genome of Drosophila melanogaster is methylated and two MBD proteins, dMBD2/3 and dMBD-R2, are present. Are Drosophila MBD proteins required for neuronal function, and as MBD-containing proteins have diverged and evolved, does the MBD domain retain the molecular properties required for conserved cellular function across species? To address these questions, we expressed the human MBD-containing protein, hMeCP2, in distinct amine neurons and quantified functional changes in sleep circuitry output using a high throughput assay in Drosophila. hMeCP2 expression resulted in phase-specific sleep loss and sleep fragmentation with the hMeCP2-mediated sleep deficits requiring an intact MBD-domain. Reducing endogenous dMBD2/3 and dMBD-R2 levels also generated sleep fragmentation, with an increase in sleep occurring upon dMBD-R2 reduction. To examine if hMeCP2 and dMBD-R2 are targeting common neuronal functions, we reduced dMBD-R2 levels in combination with hMeCP2 expression and observed a complete rescue of sleep deficits. Furthermore, chromosomal binding experiments indicate MBD-R2 and MeCP2 associate on shared genomic loci. Our results provide the first demonstration that Drosophila MBD-containing family members are required for neuronal function and suggest the MBD domain retains considerable functional conservation at the whole organism level across species.

Sleep problems in Rett syndrome animal models: A systematic review

“…Thirteen studies were identified by this systematic search as summarized in Table 1. We categorized the studies into three groups according to the species of animal used for modeling RTT, which were one on cynomolgus monkey (Y. Chen et al., 2017), two on Drosophila (Gupta, Morgan, Bailey, & Certel, 2016; Hess‐Homeier, Fan, Gupta, Chiang, & Certel, 2014), and 10 using mice (D'Cruz et al., 2010; Fuchs et al., 2018; Johnston et al., 2014; Li et al., 2015; Lo Martire et al., 2017; Moretti, Bouwknecht, Teague, Paylor, & Zoghbi, 2005; Ren, Ding, Funk, & Greer, 2012; Robinson, Plano, Cobb, & Riedel, 2013; Tsuchiya et al., 2015; Wither et al., 2012).…”

“…While, sample size was available in eight mouse studies ranging from 4 to 31. For the two studies in Drosophila, using only males, the sample size ranged between 21 to 50 (Gupta et al., 2016) and 30 (Hess‐Homeier et al., 2014).…”

“…Drosophila (Gupta, Morgan, Bailey, & Certel, 2016;Hess-Homeier, Fan, Gupta, Chiang, & Certel, 2014), and 10 using mice (D'Cruz et al, 2010;Fuchs et al, 2018;Johnston et al, 2014;Li et al, 2015;Lo Martire et al, 2017;Moretti, Bouwknecht, Teague, Paylor, & Zoghbi, 2005;Ren, Ding, Funk, & Greer, 2012;Robinson, Plano, Cobb, & Riedel, 2013;Tsuchiya et al, 2015;Wither et al, 2012).…”

Methyl-CpG binding domain proteins inhibit interspecies courtship and promote aggression in Drosophila

“…Furthermore, the methyl-CpG binding domain (MBD) retains considerable functional identity across species 39 . As MBD protein family members translate these epigenetic marks to appropriate functional states, we simply asked if MBD proteins in Drosophila contribute to setting the behavioral strategies associated with reproductive isolation as well as survival behaviors.…”

Múltiplas abordagens para determinar os fatores genéticos que contribuem para o ASD

“…Neural development of D. melanogaster is very well characterized and shows great similarity to humans (SÁNCHEZ-SORIANO et al, 2007). This organism has been successfully used in the understanding of several human neurodevelopmental conditions, such as Fragile X syndrome REEVE et al, 2005;BASSELL;SASAKI, 2009;CALLAN et al, 2010)(MONYAK et al, 2016 and other autism-related conditions, including those with mutations in NRXN1, CNTNAP2, NLGN3 and CYFIP1 (SCHENCK et al, 2003;HAHN et al, 2013;GUPTA et al, 2016;PARK et al, 2016). These research reinforce the relevance of this model organism into the study of ASD and other neurodevelopmental disorders.…”