Molecular Mechanisms Underlying Bidirectional Hair Cell Orientation and Their Contribution to Vestibular and Lateral Line Function

Core Concepts

Loss of the transcription factor GPR156 prevents the reversal of hair cell orientation in mouse otolith organs and zebrafish lateral line, but does not significantly impact hair cell physiology, afferent innervation patterns, or overall vestibular function.

Abstract

The content explores how the molecular mechanisms that confer bidirectional hair cell orientation in the vestibular system and lateral line contribute to sensory function. Key findings: In mouse otolith organs, loss of GPR156 prevents the reversal of hair cell orientation in the lateral extrastriolar (LES) region, but does not affect hair cell numbers, zonal organization, or mechanotransduction properties. Afferent innervation patterns and selectivity for hair cells of opposing orientations were preserved in the mouse utricle lacking GPR156, despite the absence of the line of polarity reversal. Afferent excitability was also unaffected. While GPR156 deletion did not impact mouse vestibular function, performance on tests engaging otolith organs was altered, suggesting the line of polarity reversal contributes to specific aspects of vestibular processing. In the zebrafish lateral line, loss of GPR156 resulted in all hair cells adopting the orientation that detects anterior flow. Importantly, this led to a reduction in the mechanosensitive responses of these hair cells compared to the larger responses of the anterior-detecting hair cells in control animals. Afferent innervation patterns and synaptic pairing were preserved in zebrafish lateral line lacking GPR156, despite the absence of hair cell orientation reversal. The results clarify how the molecular mechanisms underlying hair cell orientation reversal contribute to sensory organ function, from single cell physiology to animal behavior, in both the vestibular system and lateral line.

Stats

The maximum conductance density (Gmax/Cm) of the voltage-gated K+ currents in type I hair cells was much larger than in type II hair cells. The activation midpoint (V1/2) of the voltage-gated outward currents in type II hair cells was around -30 to -40 mV. The maximum GMET of type I hair cells was larger in the medial extrastriolar (MES) zone compared to the LES or striolar zones.

Quotes

"Loss of GPR156 does not impact HC orientation in the striola and MES, but Gpr156 is transcribed in all HCs across the maculae." "Afferent innervation patterns and selectivity for hair cells of opposing orientations were preserved in the mouse utricle lacking GPR156, despite the absence of the line of polarity reversal." "In the zebrafish lateral line, loss of GPR156 resulted in all hair cells adopting the orientation that detects anterior flow. Importantly, this led to a reduction in the mechanosensitive responses of these hair cells compared to the larger responses of the anterior-detecting hair cells in control animals."

Key Insights Distilled From

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function

by Ono,K., Jary... at www.biorxiv.org 03-29-2024

https://www.biorxiv.org/content/10.1101/2024.03.26.586740v1

Deeper Inquiries

How might the molecular mechanisms underlying hair cell orientation reversal be leveraged to develop novel therapies for vestibular and lateral line disorders

The molecular mechanisms underlying hair cell orientation reversal, particularly the EMX2-GPR156 pathway, hold great potential for the development of novel therapies for vestibular and lateral line disorders. By understanding how these transcription factors and receptors regulate the orientation of hair cells, researchers can explore targeted interventions to correct orientation abnormalities in cases where hair cells are misaligned. This could involve gene therapy approaches to restore proper EMX2 and GPR156 expression levels or to modulate downstream signaling pathways that influence hair cell orientation. Additionally, insights into how these molecular mechanisms impact afferent innervation and mechanosensitive properties can guide the development of therapies aimed at improving sensory processing and function in the vestibular system. By leveraging the knowledge gained from studying the EMX2-GPR156 pathway, researchers can potentially design innovative treatments for vestibular and lateral line disorders that target specific molecular targets to restore normal sensory function.

What other developmental or physiological processes, beyond hair cell orientation, might the EMX2-GPR156 pathway regulate in the inner ear and lateral line

The EMX2-GPR156 pathway, known for its role in hair cell orientation reversal, may also regulate other developmental and physiological processes in the inner ear and lateral line. One potential area of interest is the regulation of afferent neuron development and connectivity. Studies have shown that EMX2 is involved in directing afferent projections to specific populations of hair cells based on their orientation. Understanding how EMX2 and GPR156 influence afferent innervation patterns could provide insights into how these transcription factors contribute to the establishment of precise neural circuits in the vestibular system. Additionally, the EMX2-GPR156 pathway may play a role in modulating mechanosensitive properties beyond hair cell orientation. By influencing the expression of genes involved in mechanotransduction, EMX2 and GPR156 could impact the sensitivity and responsiveness of hair cells to mechanical stimuli. Further research is needed to explore the full extent of the regulatory functions of the EMX2-GPR156 pathway in the inner ear and lateral line.

Could the differences in mechanosensitive responses between anterior- and posterior-detecting hair cells in the lateral line serve as a model to understand how hair cell functional asymmetries contribute to sensory processing in the vestibular system

The differences in mechanosensitive responses between anterior- and posterior-detecting hair cells in the lateral line provide a valuable model for understanding how hair cell functional asymmetries contribute to sensory processing in the vestibular system. The distinct responses of these two populations of hair cells to fluid flow stimuli enable the lateral line system to detect directional cues and respond appropriately to environmental changes. By studying the molecular mechanisms that underlie these functional differences, researchers can gain insights into how hair cells encode and transmit directional information to afferent neurons. This knowledge can be applied to investigate how similar asymmetries in mechanosensitive properties of hair cells in the vestibular system contribute to the detection of head movements and orientation relative to gravity. Understanding the role of hair cell functional asymmetries in sensory processing can provide valuable insights into the neural mechanisms that underlie vestibular function and help elucidate how the brain interprets and responds to spatial orientation cues.