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.

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

“…Notably, targeted inactivation of the Tsk gene in mice causes malformation of the corpus callosum, similar to the SPOCK1 mutants [ 596 ] (see below) and agenesis of the anterior commissure [ 597 ]. This forebrain commissure formation is co-regulated by draxin, dorsal inhibitory axon guidance protein [ 598 ]. Finally, tsukushi has been shown to control the hair cycles by regulating the TGFβ1/Smad pathway [ 594 ].…”

microRNA-2110 functions as an onco-suppressor in neuroblastoma by directly targeting Tsukushi

“…The role of TSKU in regulating cell differentiation has been previously suggested in several cell types including neuronal cells [40–42]. For example, Hossain et al .…”

“…For example, Hossain et al . showed that TSKU overexpression inhibited anterior olfactory neural and cortical neurite outgrowth [40]. Niimori et al .…”

Tsukushi is essential for the development of the inner ear

“…The diverse functions of TSK depend on its ability to bind and interact with various intermediate molecules of some major signaling pathways. TSK interactions with BMP, FGF, TGF-β, and Wnt signaling pathways have been previously reported [1,[4][5][6] and shown to affect the development of the central nervous networks [7,8], as well as wound healing [9]. TSK is reportedly expressed in the chick retina [3,10], the subventricular zone and hippocampus in the mouse brain [8], and dermal hair follicles in mice [9].…”