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1.
bioRxiv ; 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38895287

ABSTRACT

Our sense of hearing is critically dependent on the spiral ganglion neurons (SGNs) that connect the sound receptors in the organ of Corti (OC) to the cochlear nuclei of the hindbrain. Type I SGNs innervate inner hair cells (IHCs) to transmit sound signals, while type II SGNs (SGNIIs) innervate outer hair cells (OHCs) to detect moderate-to-intense sound. During development, SGNII afferents make a characteristic 90-degree turn toward the base of the cochlea and innervate multiple OHCs. It has been shown that the Planar Cell Polarity (PCP) pathway acts non-autonomously to mediate environmental cues in the cochlear epithelium for SGNII afferent turning towards the base. However, the underlying mechanisms are unknown. Here, we present evidence that PCP signaling regulates multiple downstream effectors to influence cell adhesion and the cytoskeleton in cochlear supporting cells (SCs), which serve as intermediate targets of SGNII afferents. We show that the core PCP gene Vangl2 regulates the localization of the small GTPase Rac1 and the cell adhesion molecule Nectin3 at SC-SC junctions through which SGNII afferents travel. Through in vivo genetic analysis, we also show that loss of Rac1 or Nectin3 partially phenocopied SGNII peripheral afferent turning defects in Vangl2 mutants, and that Rac1 plays a non-autonomous role in this process in part by regulating PCP protein localization at the SC-SC junctions. Additionally, epistasis analysis indicates that Nectin3 and Rac1 likely act in the same genetic pathway to control SGNII afferent turning. Together, these experiments identify Nectin3 and Rac1 as novel regulators of PCP-directed SGNII axon guidance in the cochlea.

2.
eNeuro ; 11(1)2024 Jan.
Article in English | MEDLINE | ID: mdl-38164601

ABSTRACT

Declaring the 1990s as The Decade of the Brain put the field of neuroscience at the forefront of public attention, with the nervous system becoming a subject of increasing interest in popular media. Although this has generally brought large swaths of the public closer to neuroscience, most current research is published and disseminated in a single language: English. This is unsurprising as English is indeed the lingua franca in scientific circles, but people around the world communicate in many other languages. To make neuroscience accessible to a larger audience, we share an initiative to translate the Knowing Neurons platform into a second language: Spanish. This collaborative project integrates humanities and STEM academic programs to make use of bilingual university students, in association with professional linguists and neuroscientists, to translate scientific content into a relatable format to Spanish speakers regardless of their country of origin. The translation effort was piloted within the framework of undergraduate outreach courses at the University of California, Los Angeles, and is coupled with outreach components targeting the Spanish-speaking community to promote this new resource. This project aims to foster an environment where the neuroscientific interests of the public, college students, instructors, and researchers coalesce in a unified space. We hope that opening new lines of communication with traditionally underrepresented communities might help combat the persistent lack of diversity in neuroscience (and STEM) that is currently seen in academia. We also provide an outline to inspire others to translate these, and similar resources, into other languages.


Subject(s)
Language , Neurosciences , Humans , Communication , Students , Brain
3.
J Cell Biol ; 219(10)2020 10 05.
Article in English | MEDLINE | ID: mdl-32805026

ABSTRACT

In the mammalian cochlea, the planar cell polarity (PCP) pathway aligns hair cell orientation along the plane of the sensory epithelium. Concurrently, multiple cell intrinsic planar polarity (referred to as iPCP) modules mediate planar polarization of the hair cell apical cytoskeleton, including the kinocilium and the V-shaped hair bundle essential for mechanotransduction. How PCP and iPCP are coordinated during development and the roles of Wnt ligands in this process remain unresolved. Here we show that genetic blockade of Wnt secretion in the cochlear epithelium resulted in a shortened cochlear duct and misoriented and misshapen hair bundles. Mechanistically, Wnts stimulate Gi activity by regulating the localization of Daple, a guanine nucleotide exchange factor (GEF) for Gαi. In turn, the Gßγ complex signals through phosphoinositide 3-kinase (PI3K) to regulate kinocilium positioning and asymmetric localizations of a subset of core PCP proteins, thereby coordinating PCP and iPCP. Thus, our results identify a putative Wnt/heterotrimeric G protein/PI3K pathway for PCP regulation.


Subject(s)
Carrier Proteins/genetics , Cochlea/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Heterotrimeric GTP-Binding Proteins/genetics , Animals , Cell Polarity/genetics , Hair Cells, Auditory/metabolism , Macromolecular Substances/chemistry , Macromolecular Substances/metabolism , Mechanotransduction, Cellular/genetics , Mice , Microtubules/genetics , Phosphatidylinositol 3-Kinases/genetics , Wnt Signaling Pathway/genetics
4.
Proc Natl Acad Sci U S A ; 116(11): 4999-5008, 2019 03 12.
Article in English | MEDLINE | ID: mdl-30814219

ABSTRACT

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.


Subject(s)
Cell Adhesion Molecules/metabolism , Cell Polarity , Hair Cells, Auditory, Inner/cytology , Hair Cells, Auditory, Inner/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Cycle Proteins , Female , Guanine Nucleotide Exchange Factors/metabolism , Male , Mice , Microtubules/metabolism , Mosaicism , Organ of Corti/metabolism , Phosphoproteins/metabolism , Protein Binding , Protein Kinase C/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , T-Lymphoma Invasion and Metastasis-inducing Protein 1/metabolism , rac GTP-Binding Proteins/metabolism
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