scholarly journals Notch-Mediated Polarity Decisions in Mechanosensory Hair Cells

2018 ◽  
Author(s):  
A. Jacobo ◽  
A. Dasgupta ◽  
A. Erzberger ◽  
K. Siletti ◽  
A. J. Hudspeth
Keyword(s):  
Cell Polarity ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Opposite Polarity ◽  
Directional Sensitivity ◽  
Mechanical Sensitivity ◽  
Bistable Switch ◽  
Genetic Perturbations ◽  
Experimental Approaches ◽  
Mechanosensory Hair Cells

The development of mechanosensory epithelia, such as those of the auditory and vestibular systems, results in the precise orientation of mechanosensory hair cells and consequently directional sensitivity. After division of a precursor cell in the zebrafish’s lateral line, the daughter hair cells differentiate with opposite mechanical sensitivity. Through a combination of theoretical and experimental approaches, we show that Notch1a-mediated lateral inhibition produces a bistable switch that reliably gives rise to cell pairs of opposite polarity. Using our mathematical model of the process, we predict the outcome of several genetic and chemical alterations to the system, which we then confirm experimentally. We show that Notch1a downregulates the expression of Emx2, a transcription factor known to be involved in polarity specification, and acts in parallel with the planar-cell-polarity system to determine the orientation of hair bundles. By analyzing the effect of simultaneous genetic perturbations to Notch1a and Emx2 we infer that the generegulatory network determining cell polarity includes undiscovered polarity effectors.

scholarly journals Connectomics of the zebrafish's lateral-line neuromast reveals wiring and miswiring in a simple microcircuit

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eliot Dow ◽  
Adrian Jacobo ◽  
Sajjad Hossain ◽  
Kimberly Siletti ◽  
A J Hudspeth
Keyword(s):  
Hair Cell ◽  
Lateral Line ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Developmental Stages ◽  
Notch Signaling Pathway ◽  
Nerve Fibers ◽  
Directional Sensitivity ◽  
Efferent Nerve ◽  
Polarity Gene

The lateral-line neuromast of the zebrafish displays a restricted, consistent pattern of innervation that facilitates the comparison of microcircuits across individuals, developmental stages, and genotypes. We used serial blockface scanning electron microscopy to determine from multiple specimens the neuromast connectome, a comprehensive set of connections between hair cells and afferent and efferent nerve fibers. This analysis delineated a complex but consistent wiring pattern with three striking characteristics: each nerve terminal is highly specific in receiving innervation from hair cells of a single directional sensitivity; the innervation is redundant; and the terminals manifest a hierarchy of dominance. Mutation of the canonical planar-cell-polarity gene vangl2, which decouples the asymmetric phenotypes of sibling hair-cell pairs, results in randomly positioned, randomly oriented sibling cells that nonetheless retain specific wiring. Because larvae that overexpress Notch exhibit uniformly oriented, uniformly innervating hair-cell siblings, wiring specificity is mediated by the Notch signaling pathway.

scholarly journals Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

2019 ◽  
Vol 116 (11) ◽  
pp. 4999-5008 ◽  
Author(s):  
Andre Landin Malt ◽  
Zachary Dailey ◽  
Julia Holbrook-Rasmussen ◽  
Yuqiong Zheng ◽  
Arielle Hogan ◽  
...  
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Cell Polarity ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Tissue Level ◽  
Hair Bundle ◽  
Nucleotide Exchange ◽  
Genetic Mosaic ◽  
Pcp Signaling

In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3–GEF–Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.

scholarly journals Ick Ciliary Kinase Is Essential for Planar Cell Polarity Formation in Inner Ear Hair Cells and Hearing Function

2017 ◽  
Vol 37 (8) ◽  
pp. 2073-2085 ◽  
Author(s):  
Shio Okamoto ◽  
Taro Chaya ◽  
Yoshihiro Omori ◽  
Ryusuke Kuwahara ◽  
Shun Kubo ◽  
...  
Keyword(s):  
Inner Ear ◽  
Cell Polarity ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Hearing Function

scholarly journals Muscularization of the Mesenchymal Outlet Septum during Cardiac Development

2020 ◽  
Vol 7 (4) ◽  
pp. 51
Author(s):  
Maurice J. B. van den Hoff ◽  
Andy Wessels
Keyword(s):  
Cell Polarity ◽  
Essential Role ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
In Vitro Models ◽  
Outflow Tract ◽  
Heart Tube ◽  
Tgfβ Signaling ◽  
Experimental Approaches

After the formation of the linear heart tube, it becomes divided into right and left components by the process of septation. Relatively late during this process, within the developing outflow tract, the initially mesenchymal outlet septum becomes muscularized as the result of myocardialization. Myocardialization is defined as the process in which existing cardiomyocytes migrate into flanking mesenchyme. Studies using genetically modified mice, as well as experimental approaches using in vitro models, demonstrate that Wnt and TGFβ signaling play an essential role in the regulation of myocardialization. They also show the significance of the interaction between cardiomyocytes, endocardial derived cells, neural crest cells, and the extracellular matrix. Interestingly, Wnt-mediated non-canonical planar cell polarity signaling was found to be a crucial regulator of myocardialization in the outlet septum and Wnt-mediated canonical β-catenin signaling is an essential regulator of the expansion of mesenchymal cells populating the outflow tract cushions.

scholarly journals Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity

2010 ◽  
Vol 20 (3) ◽  
pp. 466-481 ◽  
Author(s):  
Daniel Jagger ◽  
Gayle Collin ◽  
John Kelly ◽  
Emily Towers ◽  
Graham Nevill ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Basal Bodies ◽  
Cochlear Hair Cells ◽  
Alström Syndrome ◽  
Alstrom Syndrome ◽  
Syndrome Protein

scholarly journals Connectomics of the zebrafish’s lateral-line neuromast reveals wiring and miswiring in a simple microcircuit

2018 ◽  
Author(s):  
Eliot Dow ◽  
Adrian Jacobo ◽  
Sajjad Hossain ◽  
Kimberly Siletti ◽  
A. J. Hudspeth
Keyword(s):  
Hair Cell ◽  
Lateral Line ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Developmental Stages ◽  
Notch Signaling Pathway ◽  
Nerve Fibers ◽  
Directional Sensitivity ◽  
Efferent Nerve ◽  
Polarity Gene

AbstractThe lateral-line neuromast of the zebrafish displays a restricted, consistent pattern of innervation that facilitates the comparison of microcircuits across individuals, developmental stages, and genotypes. We used serial blockface scanning electron microscopy to determine from multiple specimens the neuromast connectome, or comprehensive set of connections between hair cells and afferent and efferent nerve fibers. This analysis delineated a complex but consistent wiring pattern with three striking characteristics: each nerve terminal is highly specific in receiving innervation from hair cells of a single directional sensitivity; the innervation is redundant; and the terminals manifest a hierarchy of dominance. Mutation of the canonical planar-cell-polarity gene vangl2, which decouples the asymmetric phenotypes of sibling hair-cell pairs, results in randomly positioned, randomly oriented sibling cells that nonetheless retain specific wiring. Because larvae that overexpress Notch exhibit uniformly oriented, uniformly innervating hair-cell siblings, wiring specificity is mediated by the Notch signaling pathway.

scholarly journals Par3 regulates Rac1 signaling and microtubule organization during planar polarization of auditory hair cells

2018 ◽  
Author(s):  
Andre Landin Malt ◽  
Zachary Dailey ◽  
Julia Holbrook-rasmussen ◽  
Yuqiong Zheng ◽  
Quansheng Du ◽  
...  
Keyword(s):  
Inner Ear ◽  
Cell Polarity ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Tissue Level ◽  
Hair Bundle ◽  
Microtubule Organization ◽  
Reciprocal Regulation ◽  
Auditory Hair Cells ◽  
Pcp Signaling

AbstractIn the inner ear sensory epithelia, hair bundles atop sensory hair cells are mechanosensory apparati with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 plays a key role in planar polarization of hair cells. Par3 deletion in the inner ear resulted in defects in cochlear length, hair bundle orientation and kinocilium positioning. During PCP establishment, Par3 promotes localized Rac-Pak signaling through an interaction with Tiam1. Par3 regulates microtubule dynamics and organization, which is crucial for basal body positioning. Moreover, there is reciprocal regulation of Par3 and the core PCP molecule Vangl2. Thus, we conclude that Par3 is an effector and integrator of cell-intrinsic and tissue-level PCP signaling.One sentence summaryPar3 regulates planar polarity of auditory hair cells

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