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Section on Sensory Cell Development and Function
Katie Kindt, Ph.D., Acting Chief
The section on Sensory Cell Development and Function investigates how discrete subcellular signals, such as Ca2+ influx and vesicle release, shape hair cell development, and how these signals are required for proper physiological function.
In particular, our research is focused on the mechanosensory hair-cell synapse. Sensory hair-cell synapses or ribbon synapses are required to reliably transmit auditory and vestibular information to the brain. Recent evidence suggests that noise-induced and age-related hearing result from a loss of hair-cell synapses. Therefore, understanding how hair-cell synapses form and function is critical to understanding how to reform these structures after hearing loss. To study hair-cell synapse development and function, we use the zebrafish as a model system. Similar to mammals, zebrafish have sensory hair cells that enable them to sense sound and maintain proper balance. Previous work has shown that genes that cause deafness in zebrafish are also associated with hearing defects in humans and in mice. In contrast to mammals, the embryonic and larval zebrafish routinely studied are transparent and develop externally, allowing hair cells in zebrafish can be studied in vivo (figure 1).
Figure 1. Transgenic illuminates sensory hair cells in the larval zebrafish. Zebrafish have hair cells in their inner ear (A, B) and in their lateral line system (A,C). The lateral line system is composed of clusters of superficial hair cells called neuromasts that are readily visualized and physically stimulated.
In hair cells, synaptic responses are shaped by distinct sources of Ca2+: mechanosensitive Ca2+ -permeable channels in the hair bundle, voltage-gated Ca2+ channels at the synapse, and Ca2+ storage and release from mitochondria and ER. All of these Ca2+ signals shape vesicle release and are ultimately required for the proper formation and function of hair-cell synapses. To examine these complex signals in vivo, we use transgenic zebrafish to precisely monitor Ca2+ signals in the hair cell cytoplasm, hair bundle, presynaptic density, and monitor synaptic vesicle release (figure 2). We combine in vivo imaging of Ca2+ and vesicle fusion, confocal and electron microscopy, genetics, and pharmacology to characterize how discrete signals shape synapse function and development in an intact system. This long-term goal of this research is to improve our understanding of how hair-cell synapses functionally develop. This knowledge may provide insight into how to regenerate hair cell synapses after they are lost, a major barrier to restoring hearing loss.
Figure 2. Localized expression of genetically encoded indicators. Genetically encoded indicators localized to the ribbon synapse (A), hair bundle (B), and synaptic vesicles (green) and ribbon synapses (red) (C).
Left to right: Qiuxiang Zhang, Candy Wong, Mike Waltman, Sunita Warrier, Czarina Ramos, Katie Kindt, Alisha Beirl.
- Manchanda A, Chatterjee P, Bonventre JA, Haggard DE, Kindt KS, Tanguay RL, Johnson CP. Otoferlin depletion results in abnormal synaptic ribbons and altered intracellular calcium levels in zebrafish. Sci Rep. 2019 Oct 3;9(1):14273. doi: 10.1038/s41598-019-50710-2.
- Zhang Q, Li S, Wong HC, He XJ, Beirl A, Petralia RS, Wang YX, Kindt KS. Synaptically silent sensory hair cells in zebrafish are recruited after damage. Nat Commun. 2018, 9(1):1388.
- Ji YR, Jiang, T, Wu, D*, Kindt KS*. Directional selectivity of afferent neurons in zebrafish neuromasts is regulated by Emx2 in presynaptic hair cells. Elife, 2018, pii: e35796.
- Graydon CW, Manor U, Kindt KS. In vivo mobility and turnover of Ribeye at zebrafish ribbon synapses. Sci. Rep. 2017, 7(1), 7467.
- Sheets L, He X, Olt J, Trapani JG, Schreck M, Marcotti W, Nicolson T, and Kindt KS. Enlargement of ribbons in zebrafish hair cells disrupts presynaptic calcium channel clustering and exocytosis. J Neurosci. 2017, 2878-16.
- Jiang, T, Kindt KS*, Wu, D*. Transcription factor Emx2 controls stereociliary bundle orientation of sensory hair cells. Nathans J, ed. eLife. 2017; pii: e23661.
- Zhang QX, He XJ, Wong HC, Kindt KS. Functional calcium imaging in zebrafish lateral-line hair cells. Methods in Cell Biology. 2016 33: 229-252.
- Maeda R*, Kindt KS*, Mo W*, Erickson T, Thernau A, Barr-Gillespie P, Nicolson T. Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proc. Natl. Acad. Sci. 2014 111:12907-12912.
- Clemens-Grisham R, Kindt KS, Schmidt B, Nicolson T. Mutations in ap1b1 cause mistargeting of the Na+/K+-ATPase pump in sensory hair cells. PLoS One. 2013 8(4): e60866
- Sheets L, Kindt KS, Nicolson T. Presynaptic CaV1.3 channels regulate synaptic ribbon size and are required for synaptic maintenance in sensory hair cells. J Neurosci., 2012 32: 17273-17286.
- Kindt KS, Finch G, Nicolson T. Kinocilia mediate mechanosensitivity in developing zebrafish hair cells. Dev. Cell, 2012 23: 329-41.
- Kindt KS, Quast K, Giles A, Hendrey D, Nicastro I, Rankin C, Schafer W. Dopamine Mediates Context-Dependent Modulation of Sensory Plasticity in C elegans. Neuron, 2007 4: 662-76.
- Kindt KS*, Viswanath V*, Macpherson L, Quast K, Hu H, Patapoutian A, Schafer WR. Caenorhabditis elegans TRPA-1 functions in mechanosensation. Nat. Neurosci., 2007 10: 568-77.
- Kindt KS*, Tam T*, Whiteman S, Schafer WR. Serotonin promotes G(o)-dependent neuronal migration in Caenorhabditis elegans. Curr Biol., 2002. 12: 1738-47.
*Indicates equal contribution to the work in this publication.