The Transcription Factor Mef2 Links the Drosophila Core Clock to Fas2, Neuronal Morphology, and Circadian Behavior

Abstract

Summary The transcription factor Mef2 regulates activity-dependent neuronal plasticity and morphology in mammals, and clock neurons are reported to experience activity-dependent circadian remodeling in Drosophila. We show here that Mef2 is required for this daily fasciculation-defasciculation cycle. Moreover, the master circadian transcription complex CLK/CYC directly regulates Mef2 transcription. ChIP-Chip analysis identified numerous Mef2 target genes implicated in neuronal plasticity, including the cell-adhesion gene Fas2. Genetic epistasis experiments support this transcriptional regulatory hierarchy, CLK/CYC->Mef2-> Fas2, indicate that it influences the circadian fasciculation cycle within pacemaker neurons and suggest that this cycle also contributes to circadian behavior. Mef2 therefore transmits clock information to machinery involved in neuronal remodeling, which contributes to locomotor activity rhythms.

Circadian Rhythms in Rho1 Activity Regulate Neuronal Plasticity and Network Hierarchy

“…Although it was recently reported that daily changes in s-LNv termini are a cycle of fasciculation and defasciculation (Sivachenko et al, 2013), we found that s-LNvs add and lose axonal material with a 24hr rhythm.…”

“…The approaches previously used to quantify the termini of s-LNv projections detected clear time of day differences (Fernandez et al, 2008; Sivachenko et al, 2013). However, these methods are laborious and limited to two dimensions.…”

Circadian Pacemaker Neurons Change Synaptic Contacts across the Day

“…This analysis revealed that towards the end of the subjective night (CT22) PDF projections are significantly shorter than at the beginning (CT2) of the day (Figure 1C). These observations imply that mechanisms other than the proposed changes in the degree of fasciculation are recruited during circadian plasticity [8, 13]. To get a deeper insight into the nature of the phenomena we monitored the changes in brain explants kept in culture for 48 h after dissection.…”

“…This trend coincides with our observation of higher levels during the subjective morning, and lower levels at the beginning of the subjective night; however, we could not detect changes through the night, suggesting that, at least in clock neurons, there is a circadian rather than an homeostatic control of synaptic activity. Given that clock outputs are predominantly regulated at the transcriptional level [24], and that there is circadian regulation of MEF2, a transcription factor that turns on a program involved in structural remodeling [13], this correlation opens the provocative possibility that the circadian clock is controlling the ability of assembling novel synapses in particularly plastic neurons, which might become stabilized/recruited or otherwise pruned (disassembled), towards the end of the day.…”

“…It has recently been shown that MEF2, a transcription factor involved in activity-dependent neuronal plasticity and morphology in mammals [25], is circadianly regulated and mediates some of the remodeling of PDF dorsal terminals through the regulation of Fasciclin2 [13]. On the other hand, adult-specific silencing (and depolarization) of PDF neurons abolishes cycling in the number of BRP + active zones (Figure S1D-E), despite that it does not completely obliterate the remodeling of the axonal terminals [12], suggesting that some of the mechanisms underlying structural plasticity are clearly activity-independent, and are likely the result of additional clock-controlled output pathways still to be identified.…”