Function of bidirectional sensitivity in the otolith organs established by transcription factor Emx2

Ji, Young Rae; Tona, Yosuke; Wafa, Talah; Christman, Matthew E.; Tourney, Edward D.; Jiang, Tao; Ohta, Sho; Cheng, Hui; Fitzgerald, Tracy S.; Fritzsch, Bernd; Jones, Sherri M.; Cullen, Kathleen E.; Wu, Doris K.

doi:10.1038/s41467-022-33819-3

Cited by 31 publications

(24 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the utricle hair cells are oriented with their kinocilia positioned towards each other while in the saccule they point away, and the cell boundary separating these groups is called the Line of Polarity Reversal (LRP) (11). The afferent innervation of the maculae is also coordinated with the LPR and afferent neurons selectively contact hair cells located on either one side of the LPR or the other (12, 13). A similar organization of hair cells and neurons underlies the detection of fluid flow in lateral line neuromasts of teleost fish where it has been referred to as planar bipolarity (14, 15).…”

Section: Introductionmentioning

confidence: 99%

The dark kinase STK32A regulates hair cell planar polarity opposite of EMX2 in the developing mouse inner ear

Jia

Ratzan

Goodrich

et al. 2022

Preprint

View full text Add to dashboard Cite

The vestibular maculae of the inner ear contain sensory receptor hair cells that detect linear acceleration, contribute to equilibrioception, and thereby coordinate posture and ambulatory movements. These hair cells are divided between two groups, separated by a line of polarity reversal (LPR), with oppositely oriented planar-polarized stereociliary bundles that detect motion in opposite directions. The transcription factor EMX2 is known to establish this planar polarized organization by regulating the distribution of the transmembrane receptor GPR156 at the hair cell surface in one group of cells, however those genes regulated by EMX2 in this context were previously not known. We have identified the serine threonine kinase STK32A as a downstream effector negatively regulated by EMX2. Stk32a is expressed in hair cells on one side of the LPR in a pattern complementary to Emx2 due to transcriptional repression. Stk32a is necessary to align the intrinsic polarity of the bundle with the core planar cell polarity (PCP) proteins in EMX2-negative regions, and is sufficient to reorient bundles when ectopically expressed in neighboring EMX2-positive regions. We demonstrate that STK32a reinforces LPR formation by regulating the apical localization of GPR156. These observations support a model in which bundle orientation is determined through separate mechanisms in hair cells on opposite sides of the LPR, with EMX2-mediated repression of Stk32a determining the position of the LPR.

show abstract

Section: Introductionmentioning

confidence: 99%

The dark kinase STK32A regulates hair cell planar polarity opposite of EMX2 in the developing mouse inner ear

Jia

Ratzan

Goodrich

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The unique asymmetrical orientation, or polarity, of the stereocilia of hair cells determines the directional sensitivity and is pivotal for the normal functions of the vestibular system and the organ of Corti. Specifically, LPR divides the utricle into two regions (LES and S) with opposing stereocilia polarities, and loss of hair cell polarity in the LPR region is associated with vestibular deficits 47 . We therefore investigated the hair cell orientation in domains across the LPR in the utricular macula of WT and Gpr133 -/- mice at P40 (Figure 2N).…”

Section: Resultsmentioning

confidence: 99%

Force sensing GPR133 is essential for normal balance and modulates vestibular hair cell membrane excitability via Gi signaling and CNGA3 coupling

Yang,

Zhou,

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

The maintenance of normal balance sensing is a fundamental prerequisite for virtually every activity of daily life. As one set most important balance information collectors, vestibular hair cells convert mechanical stimuli from head movement into electrical signals through a mechanoelectrical transduction (MET) process. The molecular mechanism underlying equilibrioception and MET in vestibular hair cells is not well understood but is generally believed to be mediated by ion channels. However, whether these procedures are also mediated by other receptors, such as GPCRs, which are known to govern light, odorant and taste sensing, is not known. Here, by screening the expression of force-sensitive adhesion GPCRs in vestibular hair cells and phenotype profiling in animal models, we identified that a seven-transmembrane receptor, GPR133, was able to sense force in utricle hair cells and was required for maintenance of normal equilibrioception. Notably, GPR133 converted mechanical stimuli into changes in intracellular cAMP levels through Gi engagement and then modulated plasma membrane excitability and mediated MET by coupling to CNGA3 activity changes in approximately 30% of GPR133-expressing utricle hair cells. GPR133-mediated MET and its coupling with CNGA3 were recapitulated by an in vitro reconstitution system. Further chemical labeling, mass spectrometry and cryo-EM analysis provided potential structural information on force-induced GPR133 activation and Gi3 engagement. Collectively, our findings reveal the essential role of GPR133 in the maintenance of normal equilibrioception and suggest that GPCR family members can participate in the MET process in utricle hair cells through modulation of intracellular second messenger levels and ion channel coupling.

show abstract

“…In contrast to the otolith organs with polarity reversal around striola (Hammond & Whitfield, 2006; Ji et al, 2022), the hair cell polarity in the cristae is believed to be uniform in all gnathostomes, such that the hair cells are activated when endolymph flows out of the canal into the ampulla (Lewis et al, 1985). This implies that some of a uniform response of either activation or deactivation emanates from a given canal crista, depending on the direction of rotation, in all gnathostomes.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that hair cells in the macula of most vertebrates are oppositely tuned across the striola, but not in the lamprey (Hammond & Whitfield, 2006) and likely hagfish (Higuchi et al, 2019). This mirror‐image symmetry is driven by genes like Emx2 (Ji et al, 2022; Jiang et al, 2017). The striola region of the maculae represents an anatomical divide between one area in the macula that projects almost exclusively to the cerebellum and another area in the macula that projects almost exclusively to the brainstem vestibular nuclei in mice (Balmer & Trussell, 2019; Maklad & Fritzsch, 2003).…”

Section: Introductionmentioning

confidence: 99%

Hair cell morphological patterns and polarity organization in the sea lamprey vestibular cristae

Fritzsch

Kersigo

Rejent

et al. 2023

The Anatomical Record

Self Cite

View full text Add to dashboard Cite

The inner ear of the sea lamprey was examined by scanning electron microscopy, antibody labeling with tubulin, Myo7a, Spectrin, and Phalloidin stain to elucidate the canal cristae organization and the morphology and polarity of the hair cells. We characterized the hair cell stereocilia bundles and their morphological polarity with respect to the kinocilia. We identified three types of hair cells. In Type 1 hair cells, the kinocilia were slightly longer than the tallest stereocilia. This type was located along the medial bank of the crista and their polarity, based on kinocilia location, was uniformly pointed ampullipetally. Type 2 hair cells that had kinocilia that were much longer than the stereocilia, were most abundant in the central region of the crista. This type of hair cell displayed variable polarity. Type 3 hair cells had extremely long kinocilia (~40–50 μm long) and with extremely short stereocilia. They were mostly located in the lateral zone crista and displayed ampullipetal polarity. Myo7a and tubulin antibodies revealed that hair cells and vestibular afferents are distributed across the canal cristae in the lamprey, covering the area of cruciate eminence; a feature that is absent in more derived vertebrates. Spectrin shows hair cells of varying polarities in the central zone. In this zone, some cells followed the main polarity vector (lateral) like those in medial and lateral zones, whereas other cells displayed polarities that carried up to 40° from the main polarity vector.

show abstract

Function of bidirectional sensitivity in the otolith organs established by transcription factor Emx2

Cited by 31 publications

References 51 publications

The dark kinase STK32A regulates hair cell planar polarity opposite of EMX2 in the developing mouse inner ear

The dark kinase STK32A regulates hair cell planar polarity opposite of EMX2 in the developing mouse inner ear

Force sensing GPR133 is essential for normal balance and modulates vestibular hair cell membrane excitability via Gi signaling and CNGA3 coupling

Hair cell morphological patterns and polarity organization in the sea lamprey vestibular cristae

Contact Info

Product

Resources

About