Long-Chain Acyl-CoA Synthetase 4A Regulates Smad Activity and Dorsoventral Patterning in the Zebrafish Embryo

Abstract

Summary Long-chain polyunsaturated fatty acids (LC-PUFA) and their metabolites are critical players in cell biology and embryonic development. Here we show that long-chain acyl CoA synthetase 4a (Acsl4a), an LC-PUFA activating enzyme, is essential for proper patterning of the zebrafish dorsoventral axis. Loss of Acsl4a results in dorsalized embryos due to attenuated Bmp signaling. We demonstrate that Acsl4a modulates the activity of Smad transcription factors, the downstream mediators of Bmp signaling. Acsl4a promotes the inhibition of p38 MAPK and the Akt-mediated inhibition of glycogen synthase kinase 3 (GSK3), critical inhibitors of Smad activity. Consequently, introduction of a constitutively active Akt can rescue the dorsalized phenotype of Acsl4a deficient embryos. Our results reveal a critical role for Acsl4a in modulating Bmp-Smad activity and provide a potential avenue for LC-PUFAs to influence a variety of developmental processes.

Gene Expression Profile and Signaling Pathways in MCF-7 Breast Cancer Cells Mediated by Acyl-Coa Synthetase 4 Overexpression

“…In particular, the finding that cellular development and embryogenesis are within the top ten biofunctions is interestingly in agreement with recent work showing the crucial role of ACSL4 pathways in embryo development in zebrafish [12] and Drosophila [14,24].…”

“…In our studies, Wnt signaling inhibited GSK3β, which normally phosphorylates and promotes TSC2 activity, and ACSL4 overexpression produced the stimulation of GSK3 on Ser9, which suggests that this mechanism of mTORC1 activation is also used by ACSL4 [22]. As mentioned above, ACSL4 overexpression increases the phosphorylation of GSK3α and β, and a requirement for ACSL4 has recently been demonstrated in dorsoventral pattering of zebrafish embryo [12] and embryogenesis and neurogenesis in Drosophila [14,24]. These results show that ACSL4 works through the inhibition of AKT-dependent GSK3 activity by increasing its phosphorylation.…”

“…Unlike the other ACSL isoforms, ACSL4 is encoded on the X chromosome and its expression is highest in adrenal cortex, ovary and testis [6][7][8][9][10], as well as in mouse and human cerebellum and hippocampus [11]. Studies on the physiological functions of ACSL4 have revealed possible roles in polyunsaturated fatty acid metabolism in brain, in steroidogenesis, in eicosanoid metabolism related to apoptosis and embryogenesis [8][9][10][11][12][13][14]. ACSL4 expression has also been associated with non-physiological functions such as mental retardation disorder [15,16] and cancer [2,3,17,18].…”

Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish

“…Other mechanisms could contribute to the suppression of Bmp signaling. Interestingly, Miyares and coauthors46 documented the requirement for long-chain acyl-CoA synthetase 4a ( Acsl4a ) for proper Bmp signaling and patterning of the zebrafish dorso-ventral axis. G.…”

“…These features could be explained, at least in part, by the reduction in Bmp activation observed both in zebrafish and in Drosophila . The enzyme can actually control the levels of Smad transcription factors by blocking the inhibiting activity of glycogen synthase kinase 3 and p38 mitogen-activated protein kinase, as shown in zebrafish46, but can also affect vesicles trafficking and membrane recycling, and hence the availability of Bmp receptor, as observed in Drosophila 51. The reduction of CoA levels induced by down-regulation of Coasy can surely have an impact on LC-PUFA activation process and therefore affect Bmp signaling.…”