The combinatorial guidance activities of draxin and Tsukushi are essential for forebrain commissure formation

Mahmud Hossain, Giasuddin Ahmed, Iftekhar Bin Naser, Yohei Shinmyo, Ayako Ito, M. Asrafuzzaman Riyadh, Athary Felemban, Xiaohong Song, Kunimasa Ohta, Hideaki Tanaka

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11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)58-70
Number of pages13
JournalDevelopmental Biology
Volume374
Issue number1
DOIs
StatePublished - Feb 1 2013

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Keywords

  • Anterior commissure
  • Axon guidance
  • Corpus callosum
  • Draxin
  • Genetic interaction
  • Tsukushi

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Hossain, M., Ahmed, G., Bin Naser, I., Shinmyo, Y., Ito, A., Asrafuzzaman Riyadh, M., Felemban, A., Song, X., Ohta, K., & Tanaka, H. (2013). The combinatorial guidance activities of draxin and Tsukushi are essential for forebrain commissure formation. Developmental Biology, 374(1), 58-70. https://doi.org/10.1016/j.ydbio.2012.11.029