Delayed Otolith Development Does Not Impair Vestibular Circuit Formation in Zebrafish

Abstract

What is the role of normally patterned sensory signaling in development of vestibular circuits? For technical reasons, including the difficulty in depriving animals of vestibular inputs, this has been a challenging question to address. Here we take advantage of a vestibular-deficient zebrafish mutant, rock solo ^AN66 , in order to examine whether normal sensory input is required for formation of vestibular-driven postural circuitry. We show that the rock solo ^AN66 mutant is a splice site mutation in the secreted glycoprotein otogelin (otog), which we confirm through both whole genome sequencing and complementation with an otog early termination mutant. Using confocal microscopy, we find that elements of postural circuits are anatomically normal in rock solo ^AN66 mutants, including hair cells, vestibular ganglion neurons, and vestibulospinal neurons. Surprisingly, the balance and postural deficits that are readily apparent in younger larvae disappear around 2 weeks of age. We demonstrate that this behavioral recovery follows the delayed development of the anterior (utricular) otolith, which appears around 14 days post-fertilization (dpf), compared to 1 dpf in WT. These findings indicate that utricular signaling is not required for normal structural development of the inner ear and vestibular nucleus neurons. Furthermore, despite the otolith's developmental delay until well after postural behaviors normally appear, downstream circuits can drive righting reflexes within ∼1–2 days of its arrival, indicating that vestibular circuit wiring is not impaired by a delay in patterned activity. The functional recovery of postural behaviors may shed light on why humans with mutations in otog exhibit only subclinical vestibular deficits.

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