title: ZDHHC17 promotes axon outgrowth by regulating TrkA-tubulin complex formation.
abstract: Correct axonal growth during nervous system development is critical for synaptic transduction and nervous system function. Proper axon outgrowth relies on a suitable growing environment and the expression of a series of endogenous neuronal factors. However, the mechanisms of these neuronal proteins involved in neuronal development remain unknown. ZDHHC17 is a member of the DHHC (Asp-His-His-Cys)-containing family, a family of highly homologous proteins. Here, we show that loss of function of ZDHHC17 in zebrafish leads to motor dysfunction in 3-day post-fertilization (dpf) larvae. We performed immunolabeling analysis to reveal that mobility dysfunction was due to a significant defect in the axonal outgrowth of spinal motor neurons (SMNs) without affecting neuron generation. In addition, we found a similar phenotype in zdhhc17 siRNA-treated neural stem cells (NSCs) and PC12 cells. Inhibition of zdhhc17 limited neurite outgrowth and branching in both NSCs and PC12. Furthermore, we discovered that the level of phosphorylation of extracellular-regulated kinase (ERK) 1/2, a major downstream effector of tyrosine kinase (TrkA), was largely upregulated in ZDHHC17 overexpressing PC12 cells by a mechanism independent on its palmitoyltransferase (PAT) activity. Specifically, ZDHHC17 is necessary for proper TrkA-tubulin module formation in PC12 cells. These results strongly indicate that ZDHHC17 is essential for correct axon outgrowth in vivo and in vitro. Our findings identify ZDHHC17 as an important upstream factor of ERK1/2 to regulate the interaction between TrkA and tubulin during neuronal development.
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Reproductive Medical Center of Shandong University, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Infertility Center, Qilu Hospital, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Du
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China. Electronic address: xueranchen@cmpt.ac.cn.
authors.forename: Xueran
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Histology and Embryology, Shandong University School of Medicine, No. 44, Wenhua Xi Road, Jinan, Shandong 250012, PR China. Electronic address: aijunhao@sdu.edu.cn.
authors.forename: Aijun
authors.initials: A
authors.lastname: Hao
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007814:Larva; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000494:pharmacology; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects; D009069:Movement Disorders / Q000235:genetics; D020932:Nerve Growth Factor / Q000494:pharmacology; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D009025:Morpholines; D014404:Tubulin; D020932:Nerve Growth Factor; D000217:Acyltransferases; D020917:Receptor, trkA; C569387:Zdhhc17 protein, mouse
keywords: Axon outgrowth; ERK1/2; TrkA; Tubulin; ZDHHC17