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Cell-Type–Specific Roles of Na /K Atpase Subunits in Drosophila Auditory Mechanosensation

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Cell-Type–Specific Roles of Na /K Atpase Subunits in Drosophila Auditory Mechanosensation Cell-type–specific roles of Na+/K+ ATPase subunits in Drosophila auditory mechanosensation Madhuparna Roy, Elena Sivan-Loukianova, and Daniel F. Eberl1 Department of Biology, The University of Iowa, Iowa City, IA 52242 Edited by Charalambos P. Kyriacou, University of Leicester, Leicester, United Kingdom, and accepted by the Editorial Board November 22, 2012 (received for review May 27, 2012) Ion homeostasis is a fundamental cellular process particularly a proximal axon (Fig. 1A). The scolopale cell, a principal support important in excitable cell activities such as hearing. It relies on cell, encloses the neuronal dendrites in a fluid-filled lumen, the + + the Na /K ATPase(alsoreferredtoastheNapump),whichis scolopale space. This fluid, the receptor lymph, resembles co- α β chlear endolymph and, like the endolymph, is believed to be rich composed of a catalytic subunit and a subunit required for its + transport to the plasma membrane and for regulating its activity. in K ions (7). The scolopale cells are structurally enforced with We show that α and β subunits are expressed in Johnston’sorgan actin-based scolopale rods. Auditory mechanosensation involves (JO), the Drosophila auditory organ. We knocked down expression the transduction of the mechanical sound stimulus (10) through of α subunits (ATPα and α-like) and β subunits (nrv1, nrv2,andnrv3) the rotation of distal antennal segments into a neuronal response individually in JO with UAS/Gal4-mediated RNAi. ATPα shows ele- in JO (11). Using electrophysiological techniques we can record vated expression in the ablumenal membrane of scolopale cells, sound-evoked potentials (SEPs) from the auditory nerve (9, 12). which enwrap JO neuronal dendrites in endolymph-like compart- The JO also mediates gravity and wind detection, in addition to auditory mechanosensation (13–15). ments. Knocking down ATPα,butnotα-like, in the entire JO or only fi We used the auditory mechanosensory system of Drosophila in scolopale cells using speci c drivers, resulted in complete deaf- melanogaster, with its molecular genetic and electrophysiological ness. Among β subunits, nrv2 is expressed in scolopale cells and nrv3 nrv2 techniques, to understand the role of the Na pump in maintaining in JO neurons. Knocking down in scolopale cells blocked Nrv2 auditory ion homeostasis. Our hypothesis is that the Na pump is α expression, reduced ATP expression in the scolopale cells, and important in maintaining the ion homeostasis of the auditory re- caused almost complete deafness. Furthermore, knockdown of ei- ceptor lymph. We show that ATPα is the sole Na pump α subunit in CELL BIOLOGY ther nrv2 or ATPα specifically in scolopale cells causes abnormal, JO and that it has elevated expression in scolopale cells. The β electron-dense material accumulation in the scolopale space. Simi- subunits show cell-type specific expression and functions in JO, larly, nrv3 functions in JO but not in scolopale cells, suggesting neu- with nrv2 being specific to scolopale cells and nrv3 specificto ron specificity that parallels nrv2 scolopale cell–specific support of neurons. We also show that ATPα preferentially localizes to the the catalytic ATPα. Our studies provide an amenable model to inves- scolopale cell ablumenal membrane. Such functional pump local- + tigate generation of endolymph-like extracellular compartments. ization is consistent with a role in pumping K ions into the sco- lopale cell en route to the receptor lymph, a role that resembles its receptor lymph | chordotonal organ | scolopidium | sensory cilium | contribution to generating vertebrate inner ear endolymph. scala media Results sing the energy of ATP hydrolysis, the Na pump extrudes cy- ATPα Is Expressed in JO Scolopidia and Required for Hearing. Dro- + + α α toplasmic Na (out) and extracellular K (in) in a 3:2 ratio and sophila has three subunit genes, ATP , JYalpha, and CG3701. U α maintains the gradient of these cations across the membrane (1, 2), ATP encodes at least nine mRNA isoforms (16). JYalpha is fi thus controlling the electrolytic and fluid balance in the cells and testes-speci c and has been linked to the mechanism for hybrid organs throughout the body (1). Among its other functions, the Na sterility between D. melanogaster and Drosophila simulans (17) pump helps maintain the resting potential of cells, regulates cellular and CG3701 is an α-like subunit with low expression in adult and volume, and facilitates transport of solutes in and out of cells. Ion pupal stages but moderate expression in testis (18). In adult flies, homeostasis of most biological systems depends on the Na pump. ATPα is expressed in the eye and brain (Fig. S1A), consistent In the auditory system, this pump has been linked to the mainte- with other studies (19), and in JO (Fig. 1B). nance of the inner ear osmotic balance (3). The scala media of the ATPα is expressed in the plasma membrane of JO neurons and + inner ear is filled with a K -rich extracellular fluid known as en- much more abundantly in scolopale cells (Fig. 1 B and C). To dolymph, which is essential for preserving the sensory structures determine if ATPα is functionally important in JO scolopidia, we and supporting transduction. Maintaining the endolymph homeo- wanted to test hearing in flies carrying ATPα mutations. However, stasis is critical to sustain auditory functions. Loss of endolymphatic ATPα mutants are homozygous lethal at early larval stages (20, balance causes collapse of the endolymphatic compartment, lead- 21). To circumvent these limitations, we used RNAi to knock + ing to hearing loss in mammals (4). K channels and pumps, in- down ATPα using the Gal4/UAS system (22, 23). We used ato- + cluding the Na pump, ensure proper cycling and secretion of K Gal4 (Fig. S2A) to drive expression of double-stranded RNA ions in the stria vascularis cells of the cochlea. The Na pump has under UAS control in the JO sense organ precursor cells to knock also been linked to age-related hearing loss (5) and Ménière dis- down ATPα only in these cells and their progeny. Knockdown ease (6). A detailed functional analysis of this pump is therefore animals were deaf, with complete loss of SEPs (Fig. 2). necessary to gain insight into the molecular physiology of hearing loss resulting from loss of auditory ionic homeostasis. Although vertebrate and invertebrate auditory systems differ Author contributions: M.R., E.S.-L., and D.F.E. designed research; M.R., E.S.-L., and D.F.E. structurally, they evolved from the same primitive mechanosensors performed research; M.R., E.S.-L., and D.F.E. analyzed data; and M.R. and D.F.E. wrote (7, 8), and there are striking developmental genetic similarities the paper. between the two lineages. The fly auditory organ, Johnston’s organ The authors declare no conflict of interest. (JO), is a chordotonal organ (cho) housed in the second antennal This article is a PNAS Direct Submission. C.P.K. is a guest editor invited by the segment (9). The JO comprises an array of ∼250 auditory units or Editorial Board. scolopidia. Each scolopidium comprises two to three ciliated sen- 1To whom correspondence should be addressed. E-mail: [email protected]. sory neurons associated with several support cells. These bipolar This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. neurons are monodendritic with a single distal cilium and 1073/pnas.1208866110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1208866110 PNAS Early Edition | 1of6 Downloaded by guest on October 4, 2021 required in the scolopale cells. To distinguish whether this re- quirement is developmental or physiological, we used Gal80ts,a temperature-sensitive repressor of Gal4, for temporal control. Conditions that prevent RNAi knockdown during development (18 °C) but allow it for 3 d at the adult stage (30 °C) resulted in significant hearing reduction compared with genotypically identi- cal flies raised and maintained at 18 °C (Fig. S3). Thus, ATPα function is required at the adult stage after development is com- plete. ATPα is also required during development as flies raised at 30 °C and switched to 18 °C at adulthood are not rescued (Fig. S3). EM indicated abnormal accumulation of electron-dense mate- rial in the JO scolopale space in knockdown animals (Fig. 3 D and G). This material included membrane-bound organelles such α as mitochondria. To determine if such morphological defects af- Fig. 1. ATP is expressed in JO, with highest expression in scolopale cells. fected extracellular proteins known to be present in the scolopale (A) Diagram of a single JO scolopidium showing sensory neurons and sup- port cells with important structural features. (B) Confocal image showing space, we examined Eyeshut/Spacemaker (Eys) protein (25, 26), ATPα protein expression in JO, stained with α5 monoclonal antibody (green). which localizes in the scolopale space (27), but found no differ- ATPα is specifically expressed in the neuron (N) cell body and the scolopale ences compared with control (Fig. S4). cell (S) as indicated by the white brackets. (C) Magnified image of JO sco- lopidia showing ATPα expression specifically in scolopale cells (white arrows) Functional Importance of ATPα. Campaniform and bristle organ and in the plasma membrane of neurons (white arrowhead). α5 (green) receptor lymph, and likely that of cho organs, is thought to be rich + counterstained with Texas Red phalloidin (magenta) labeling the actin in in K , resembling vertebrate inner ear endolymph (7). Therefore, + scolopale rods. (Scale bars: B and C, 10 and 5 μm, respectively.) our model is that the Na pump actively transports K ions toward the JO scolopale space. However, the Na pump is also essential for septate junction formation in a pump-independent manner Next we used UAS-RNAi against the α-like subunit (CG3701) (28, 29). Septate junctions are critical to maintain luminal integrity using the same ato-Gal4 driver.
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