title: The combinatorial guidance activities of draxin and Tsukushi are essential for forebrain commissure formation.
abstract: We have shown that draxin is a repulsive axon guidance molecule for a variety of neuron classes and that genetic deletion of draxin in mice results in the absence of all forebrain commissures. Moreover, we also identified a secreted molecule, Tsukushi (TSK), that belongs to the small leucine-rich proteoglycan family (SLRP) and inhibits signaling molecules, such as BMP and Wnt. TSK knockout mice show malformation of the corpus callosum (CC) and agenesis of the anterior commissure (AC), suggesting the importance of TSK function in forebrain commissure formation. There is a possibility that the combined function of these two proteins is essential for the formation of these commissures. In this study, we investigate this possibility by generating draxin/TSK doubly heterozygous mice and comparing their forebrain commissure phenotypes with those of singly heterozygous mice. We found that, although draxin and TSK did not interact directly, their genetic interaction was evident from the significantly higher prevalence of CC malformation and agenesis of the AC in the draxin/TSK doubly heterozygous mice. Importantly, in this study, we demonstrated a new function of TSK in guiding anterior olfactory neuronal (AON) and cortical axons. TSK bound to and provided growth inhibitory signals dose-dependently to AON and cortical axons in outgrowth assay. TSK also induced growth cone collapse when applied acutely to these cultured neurons. Furthermore, TSK and draxin had additive effects in inhibiting cortical and AON neurite outgrowth. Thus, based on a combination of genetic analyses and in vitro experiments, we propose that the combined guidance activities of draxin and TSK regulate forebrain commissure formation.
authors.affiliation: Department of Developmental Neurobiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Mahmud
authors.initials: M
authors.lastname: Hossain
authors.forename: Giasuddin
authors.initials: G
authors.lastname: Ahmed
authors.forename: Iftekhar Bin
authors.initials: IB
authors.lastname: Naser
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shinmyo
authors.forename: Ayako
authors.initials: A
authors.lastname: Ito
authors.forename: M Asrafuzzaman
authors.initials: MA
authors.lastname: Riyadh
authors.forename: Athary
authors.initials: A
authors.lastname: Felemban
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Song
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Ohta
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003337:Corpus Callosum / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D010641:Phenotype; D016548:Prosencephalon / Q000378:metabolism*; D011509:Proteoglycans / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011509:Proteoglycans; C534831:draxin protein, mouse; C554950:tsukushi protein, mouse