Disorganized Innervation and Neuronal Loss in the Inner Ear of Slitrk6-Deficient Mice

Abstract

Slitrks are type I transmembrane proteins that share conserved leucine-rich repeat domains similar to those in the secreted axonal guidance molecule Slit. They also show similarities to Ntrk neurotrophin receptors in their carboxy-termini, sharing a conserved tyrosine residue. Among 6 Slitrk family genes in mammals, Slitrk6 has a unique expression pattern, with strong expression in the sensory epithelia of the inner ear. We generated Slitrk6-knockout mice and investigated the development of their auditory and vestibular sensory organs. Slitrk6-deficient mice showed pronounced reduction in the cochlear innervation. In the vestibule, the innervation to the posterior crista was often lost, reduced, or sometimes misguided. These defects were accompanied by the loss of neurons in the spiral and vestibular ganglia. Cochlear sensory epithelia from Slitrk6-knockout mice have reduced ability in promoting neurite outgrowth of spiral ganglion neurons. Indeed the Slitrk6-deficient inner ear showed a mild but significant decrease in the expression of Bdnf and Ntf3, both of which are essential for the innervation and survival of sensory neurons. In addition, the expression of Ntrk receptors, including their phosphorylated forms was decreased in Slitrk6-knockout cochlea. These results suggest that Slitrk6 promotes innervation and survival of inner ear sensory neurons by regulating the expression of trophic and/or tropic factors including neurotrophins from sensory epithelia.

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

“…GO analyses of the TCCS that was highly expressed in ACC showed significant enrichment in genes associated with the Notch and Wnt pathways ( Table 2) that have previously been associated with neuron differentiation and cancer. [31][32][33] Within TCCS, neural crest stem cell markers SOX10, 34 MAP2, 35 SALL2 36 and SLITRK6, 37 as well as melanoma markers SHC4 38 and MUM1 39 were also identified. Close co-expression of FGFR1 and EFNB3 with TrkC suggested possible co-function of these receptors in ACC.…”

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…Northern blot analyses have shown that Slitrk1, -2 and -4 transcripts are detectable as early as embryonic day 11.5/12.5 . Mouse Slitrk6 expression is restricted to selected areas of the nervous system (namely, thalamus, lateral geniculate nucleus, and auditory and vestibular system of the ear), an expression pattern that is unique among Slitrks Beaubien et al, 2009;Katayama et al, 2009). Human Slitrk1-5 mRNAs are widely expressed in various brain regions, whereas Human Slitrk6 mRNA is highly expressed in the putamen, but not in the cortex .…”

“…Slitrks have been implicated in the modulation of neurite outgrowth Katayama et al, 2010;Martyen et al, 2011), the promotion of neuron survival (Katayama et al, 2009), and synapse formation (Proenca et al, 2011). Overexpression of each Slitrk member, except Slitrk1 or -4, was shown to decrease the number of neurites in PC12 cells upon nerve growth factor (NGF) treatment .…”

“…Mutation of this serine residue to alanine was shown to abolish the interaction of Slitrk1 with 14-3-3 proteins, and block the induction of neurite outgrowth in cultured mouse neurons (Kajiwara et al, 2009). Studies using knockout mice have implicated Slitrk5 in the dendritic complexity of medium spiny neurons of the adult striatum (Shmelkov et al, 2010), and showed that Slitrk6 exerts trophic actions (Katayama et al, 2009). Slitrk6-knockout mice also exhibit marked cell death in the spiral and vestibular ganglia (Katayama et al, 2009).…”

“…Studies using knockout mice have implicated Slitrk5 in the dendritic complexity of medium spiny neurons of the adult striatum (Shmelkov et al, 2010), and showed that Slitrk6 exerts trophic actions (Katayama et al, 2009). Slitrk6-knockout mice also exhibit marked cell death in the spiral and vestibular ganglia (Katayama et al, 2009). Consistent with these latter findings, both brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) mRNA levels, as well as those of their receptors, are downregulated in the inner ear of Slitrk6-knockout mice.…”