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Zebrafish rgs4 is essential for motility and axonogenesis mediated by Akt signaling

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Abstract

The schizophrenia susceptibility gene, Rgs4, is one of the most intensively studied regulators of G-protein signaling members, well known to be fundamental in regulating neurotransmission. However, little is known about its role in the developing nervous system. We have isolated zebrafish rgs4 and shown that it is transcribed in the developing nervous system. Rgs4 knockdown did not affect neuron number and patterning but resulted in locomotion defects and aberrant development of axons. This was confirmed using a selective Rgs4 inhibitor, CCG-4986. Rgs4 knockdown also attenuated the level of phosphorylated-Akt1, and injection of constitutively-activated AKT1 rescued the motility defects and axonal phenotypes in the spinal cord but not in the hindbrain and trigeminal neurons. Our in vivo analysis reveals a novel role for Rgs4 in regulating axonogenesis during embryogenesis, which is mediated by another schizophrenia-associated gene, Akt1, in a region-specific manner.

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Acknowledgments

We thank Jin-Chung Chen, Hung-Li Wang and Rong-Chi Huang for discussions, Chang-Jen Huang for Tg(huC:eGFP) line, Hitoshi Okamoto for Tg(islet1:GFP) line, Min-Chi Chen for statistical analysis, Pierre Drapeau and Hey-Jen Tsay for behavior analysis, Jim-Tong Horng for western blot, Chung-Der Hsaio for ca-AKT, and David Wilkinson for neurogenin1 and pax2a constructs for riboprobes. We are also grateful to Taiwan Zebrafish Core facility at ZeTH and Zebrafish Core in Academia Sinica for providing fish. This work was supported by grants from Chang Gung Memorial Hospital (CMRPD170513 and CMRPD1B0251) and the National Science Council of Taiwan (96-2745-B-182-003-URD).

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Authors and Affiliations

  1. Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383, Taiwan

    Yi-Chuan Cheng, Sheng-Jia Lin, Hung-Yu Shih, Fu-Yu Hsieh, Hui-Lan Wu, Chu-Li Tsao & Chia-Jung Shen

  2. Children’s Brain Tumour Research Centre, Centre for Genetics and Genomics, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    Paul J. Scotting

  3. Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 40201, Taiwan

    Li-Sung Hsu

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  1. Yi-Chuan Cheng
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Correspondence to Yi-Chuan Cheng.

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S.-J. Lin, H.-Y. Shih and F.-Y. Hsieh contributed equally to this work.

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Cheng, YC., Scotting, P.J., Hsu, LS. et al. Zebrafish rgs4 is essential for motility and axonogenesis mediated by Akt signaling. Cell. Mol. Life Sci. 70, 935–950 (2013). https://doi.org/10.1007/s00018-012-1178-z

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