title: SPIG1 negatively regulates BDNF maturation.
abstract: We previously identified SPARC-related protein-containing immunoglobulin domains 1 (SPIG1, also known as Follistatin-like protein 4) as one of the dorsal-retina-specific molecules expressed in the developing chick retina. We here demonstrated that the knockdown of SPIG1 in the retinal ganglion cells (RGCs) of developing chick embryos induced the robust ectopic branching of dorsal RGC axons and failed to form a tight terminal zone at the proper position on the tectum. The knockdown of SPIG1 in RGCs also led to enhanced axon branching in vitro. However, this was canceled by the addition of a neutralizing antibody against brain-derived neurotrophic factor (BDNF) to the culture medium. SPIG1 and BDNF were colocalized in vesicle-like structures in cells. SPIG1 bound with the proform of BDNF (proBDNF) but very weakly with mature BDNF in vitro. The expression and secretion of mature BDNF were significantly decreased when SPIG1 was exogenously expressed with BDNF in HEK293T or PC12 cells. The amount of mature BDNF proteins as well as the tyrosine phosphorylation level of the BDNF receptor, tropomyosin-related kinase B (TrkB), in the hippocampus were significantly higher in SPIG1-knockout mice than in wild-type mice. Here the spine density of CA1 pyramidal neurons was consistently increased. Together, these results suggest that SPIG1 negatively regulated BDNF maturation by binding to proBDNF, thereby suppressing axonal branching and spine formation.
authors.affiliation: Division of Molecular Neurobiology, National Institute for Basic Biology, and School of Life Science, Graduate University for Advanced Studies, Okazaki, Aichi 444-8787, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Suzuki
authors.forename: Masahito
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujikawa
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kuboyama
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yonehara
authors.forename: Takafumi
authors.initials: T
authors.lastname: Shintani
authors.forename: Hiraki
authors.initials: H
authors.lastname: Sakuta
authors.forename: Masaharu
authors.initials: M
authors.lastname: Noda
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000596:Amino Acids; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C503127:Sparcl1 protein, mouse; C098463:dolaisoleucine; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: BDNF; BDNF maturation; SPIG; axon branching; follistatin-like protein; spine formation