Interactions between the circadian clock and TGF-β signaling pathway in zebrafish

Abstract

BackgroundTGF-β signaling is a cellular pathway that functions in most cells and has been shown to play a role in multiple processes, such as the immune response, cell differentiation and proliferation. Recent evidence suggests a possible interaction between TGF-β signaling and the molecular circadian oscillator. The current study aims to characterize this interaction in the zebrafish at the molecular and behavioral levels, taking advantage of the early development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines.ResultsSmad3a, a TGF-β signaling-related gene, exhibited a circadian expression pattern throughout the brain of zebrafish larvae. Both pharmacological inhibition and indirect activation of TGF-β signaling in zebrafish Pac-2 cells caused a concentration dependent disruption of rhythmic promoter activity of the core clock gene Per1b. Inhibition of TGF-β signaling in intact zebrafish larvae caused a phase delay in the rhythmic expression of Per1b mRNA. TGF-β inhibition also reversibly disrupted, phase delayed and increased the period of circadian rhythms of locomotor activity in zebrafish larvae.ConclusionsThe current research provides evidence for an interaction between the TGF-β signaling pathway and the circadian clock system at the molecular and behavioral levels, and points to the importance of TGF-β signaling for normal circadian clock function. Future examination of this interaction should contribute to a better understanding of its underlying mechanisms and its influence on a variety of cellular processes including the cell cycle, with possible implications for cancer development and progression.

A role for TGFβ signalling in medium spiny neuron differentiation of human pluripotent stem cells

“…Previous research suggests that Alantolactone indirectly activates Smad2/3 signalling downstream of Activin by making ActR-II more bioavailable [17]. A recent study in zebrafish demonstrated that Alantolactone activated TGFβ signalling in a concentration-dependent manner to subsequently cause disruption of the circadian clock [25]. This is in line with our observations of similar Activin-and Alantolactone-induced increases in pSMAD2/3 levels and a dose-dependent effect of Alantolactone on efficiency of MSN differentiation.…”

Circadian rhythms in zebrafish (Danio rerio) behaviour and the sources of their variability

“…After translation, Per2 and Cry1a proteins dimerize and translocate to the nucleus where they interact directly with the CLOCK: BMAL heterodimer, thereby inhibiting its transcriptional activation including the transcription of Per2 and Cry1a (Frøland Steindal & Whitmore, 2019). This cycle takes about 24 h and drives dependent circadian processes in cells by regulating the expression of transcription factors that then control numerous target genes (Li et al, 2013;Sloin et al, 2018;Ramasamy et al, 2019). It should be noted that due to duplication events that occurred during teleost evolution (Liu et al, 2015), the zebrafish genome contains several homologs of known clock genes, among which Per2 and Cry1a act as components of the core clock mechanism (Ziv et al, 2005;Tamai, Young & Whitmore, 2007;Vatine et al, 2009); Cry2a and Cry2b are induced by both the CLOCK:BMAL complex and also by light; while Cry1b, Per1a, Per1b, and Per3 are induced by the CLOCK:BMAL complex but not by light (Hirayama et al, 2019).…”

Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain

“…Unique MF GO-terms included various signaling pathways and receptor activity such as Wnt/Frizzled binding (dRGC1), epinephrine binding (mRGC1), collagen binding (vRGC1), retinoic acid binding (vRGC2), chromatin binding (NB), insulin binding (NE), and glutamate receptor binding (GIs+) (Figure 3G, Dataset S1H). Many of these signaling pathways were shown to be required for normal functioning and plasticity of the zebrafish brain (Bhattarai et al, 2016b; Diotel et al, 2013; Jiao et al, 2011; Shimizu et al, 2018; Sloin et al, 2018; Tallafuss et al, 2015; Than-Trong et al, 2018); however, their specific involvement for certain subtypes of NSPCs was not shown before. Therefore, our results provide a detailed resource on specific molecular regulatory networks, constitute a starting point for underlying the heterogeneity of the NSPC populations, and serves as a comprehensive repository for researchers interested in certain molecular programs.…”