Quantitative videomicroscopy reveals latent control of cell-pair rotations in vivo DOI Creative Commons

Eva L. Kozak,

Jerónimo R. Miranda-Rodríguez, Augusto Borges

et al.

Development, Journal Year: 2023, Volume and Issue: 150(9)

Published: March 22, 2023

ABSTRACT Collective cell rotations are widely used during animal organogenesis. Theoretical and in vitro studies have conceptualized rotating cells as identical rigid-point objects that stochastically break symmetry to move monotonously perpetually within an inert environment. However, it is unclear whether this notion can be extrapolated a natural context, where ephemeral heterogeneous cellular cohorts interact with active epithelium. In zebrafish neuromasts, nascent sibling hair invert positions by ≤180° around their geometric center after acquiring different identities via Notch1a-mediated asymmetric repression of Emx2. Here, we show multicellular rotation three-phasic movement progresses coherent homotypic coupling heterotypic junction remodeling. We found no correlation between epithelium-wide flow or anisotropic resistive forces. Moreover, the Notch/Emx2 status dyad does not determine interactions surrounding Aided computer modeling, suggest initial stochastic inhomogeneities generate metastable state poises spontaneous intercellular coordination resulting instabilities enables persistently directional rotations, whereas Notch1a-determined breaking buffers rotational noise.

Language: Английский

Genetic association analysis of 77,539 genomes reveals rare disease etiologies DOI Creative Commons
Daniel Greene, Daniela Pirri, Karen Frudd

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(3), P. 679 - 688

Published: March 1, 2023

Abstract The genetic etiologies of more than half rare diseases remain unknown. Standardized genome sequencing and phenotyping large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient powerful analytical methods. We built a compact database, ‘Rareservoir’, containing variant genotypes phenotypes 77,539 participants sequenced by 100,000 Genomes Project. then used Bayesian association method BeviMed to infer associations between genes each 269 disease classes assigned clinicians participants. identified 241 known 19 previously unidentified associations. validated with ERG , PMEPA1 GPR156 searching pedigrees in other using bioinformatic experimental approaches. evidence that (1) loss-of-function variants Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene lead primary lymphoedema, (2) truncating last exon transforming growth factor-β regulator result Loeys–Dietz syndrome (3) give rise recessive congenital hearing impairment. Rareservoir provides lightweight, flexible portable system synthesizing phenotypic data required study tens thousands

Language: Английский

Citations

52
The Role of G Protein–Coupled Receptors and Receptor Kinases in Pancreaticβ-Cell Function and Diabetes DOI Creative Commons
Matthew J. Varney, Jeffrey Benovic

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(2), P. 267 - 299

Published: Jan. 30, 2024

Type 2 diabetes mellitus (T2D) has emerged as a major global health concern that accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels stem from the inability of pancreas make enough insulin meet demand. While medication can help maintain normal with chronic disease, many these medicines are outdated, severe side effects, often become less efficacious over time necessitating need for therapy. G protein-coupled receptors (GPCRs) regulate physiological processes including levels. In pancreatic β-cells, GPCRs β-cell growth, apoptosis, secretion which all critical maintaining sufficient mass output ensure euglycemia. years, new insight into signaling incretin other underscored potential desirable targets treatment diabetes. The is modulated by GPCR kinases (GRKs) phosphorylate agonist activated marking receptor arrestin binding internalization. Interestingly, genome wide association studies (GWAS) using diabetic patient cohorts link GRKs arrestins T2D. Moreover, reports show expressed serve role regulation function growth both dependent independent pathways. this review, we describe importance GRK modulating physiology. Significance Statement Pancreatic β-cells contain diverse array been shown improve survival, yet only handful successfully targeted This review discusses advances our understanding pharmacology while also highlighting necessity investigating islet enriched largely unexplored unveil novel strategies.

Language: Английский

Citations

21
A force-sensitive adhesion GPCR is required for equilibrioception DOI Creative Commons
Zhao Yang, Shuhua Zhou, Qiyue Zhang

et al.

Cell Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Equilibrioception (sensing of balance) is essential for mammals to perceive and navigate the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells crucial detecting position motion. Here, we identify G protein-coupled receptor (GPCR) LPHN2/ADGRL2, expressed on apical membrane utricular cells, as maintaining normal balance. Loss LPHN2 specifically impaired both balance behavior MET mice. Functional analyses using hair-cell-specific Lphn2 -knockout mice an LPHN2-specific inhibitor suggest that regulates tip-link-independent currents at surface cells. Mechanistic studies a heterologous system show converts force stimuli into increased open probability transmembrane channel-like protein 1 (TMC1). LPHN2-mediated sensation triggers glutamate release calcium signaling Importantly, reintroducing -deficient restores function response. Our data reveal mechanosensitive GPCR required equilibrioception.

Language: Английский

Citations

4
Diversity matters — extending sound intensity coding by inner hair cells via heterogeneous synapses DOI Creative Commons
Tobias Moser,

Nare Karagulyan,

Jakob Neef

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(23)

Published: Oct. 6, 2023

Abstract Our sense of hearing enables the processing stimuli that differ in sound pressure by more than six orders magnitude. How to process a wide range stimulus intensities with temporal precision is an enigmatic phenomenon auditory system. Downstream dynamic compression active cochlear micromechanics, inner hair cells (IHCs) cover full intensity input. Yet, firing rate each their postsynaptic spiral ganglion neurons (SGNs) encodes only fraction it. As population, respective individual coding fractions entire audible range. such “dynamic fractionation” arises topic current research and focus this review. Here, we discuss mechanisms for generating diverse functional properties SGNs formulate testable hypotheses. We postulate interplay synaptic heterogeneity, molecularly distinct subtypes SGNs, efferent modulation serves neural decomposition information thus contributes population code intensity.

Language: Английский

Citations

42
Bioinspired Wearable Thermoelectric Device Constructed with Soft‐Rigid Assembly for Personal Thermal Management DOI
Bo Wu, Yujie Lin,

Yuqing Tian

et al.

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(37)

Published: May 7, 2024

Abstract The development of high‐performance thermoelectric devices (TEDs) with personal thermoregulation is crucial for the advancement next‐generation wearable technologies. Most efforts focus on optimizing mechanical flexibility in fully encapsulated devices, but parasitic heat loss induced by layer‐packed polymer matrices high thermal impedance typically leads to degradation sensing and bidirectional conversion capabilities. Here, a bioinspired architectural strategy proposed this problem that demonstrates feasibility single‐sided assembly based soft‐rigid “skin‐spine” configuration improve utilization efficiency. With active TE units connected via serpentine electrodes, skin‐spine‐structured (SSSW‐TEDs) are successfully fabricated enabling temperature heat‐to‐electricity under mild forced convection. This contributes significant enhancements power delivery (by 300%) cost‐benefit analysis 100%) through efficient air convection dissipation. Moreover, SSSW‐TED enables regulation harnessing body heat, cooling skin, perceiving behaviors such as touching blowing. study not only provides novel insights TEDs also lays foundation widespread implementation skin thermoregulation.

Language: Английский

Citations

14
Function of bidirectional sensitivity in the otolith organs established by transcription factor Emx2 DOI Creative Commons

Young Rae Ji,

Yosuke Tona, Talah Wafa

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 24, 2022

Otolith organs of the inner ear are innervated by two parallel afferent projections to brainstem and cerebellum. These innervations were proposed segregate across line polarity reversal (LPR) within each otolith organ, which divides organ into regions hair cells (HC) with opposite stereociliary orientation. The relationship functional significance these anatomical features not known. Here, we show regional expression Emx2 in organs, establishes LPR, mediates neuronal segregation LPR constitutes bidirectional sensitivity function. Conditional knockout (cKO) HCs lacks LPR. Tmie cKO, mechanotransduction was abolished selectively domain also sensitivity. Analyses both mutants indicate that is specifically required for mice swim comfortably traverse a balance beam efficiently, but stay on rotating rod.

Language: Английский

Citations

33
Cholesterol in Class C GPCRs: Role, Relevance, and Localization DOI Creative Commons
Ugochi H. Isu, Shadi A. Badiee, Ehsaneh Khodadadi

et al.

Membranes, Journal Year: 2023, Volume and Issue: 13(3), P. 301 - 301

Published: March 3, 2023

G-protein coupled receptors (GPCRs), one of the largest superfamilies cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled operate membranes rich cholesterol, with an imbalance cholesterol level within vicinity GPCR transmembrane domains affecting structure and/or function many GPCRs, a phenomenon has been linked to several diseases. These effects could result indirect changes by altering mechanical properties lipid environment or direct binding specific sites on protein. There number studies and reviews how modulates class A GPCRs; however, this area study is yet be explored for C which characterized large extracellular region often form constitutive dimers. This review highlights interaction, functions, structural dynamics involved recognition GPCRs. We summarize recent data from some typical family members explain features functions GPCRs speculate their corresponding therapeutic potential.

Language: Английский

Citations

17
Non-canonical G protein signaling DOI Creative Commons
Bernd Nürnberg, Sandra Beer‐Hammer, Ellen Reisinger

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 255, P. 108589 - 108589

Published: Jan. 29, 2024

The original paradigm of classical - also referred to as canonical cellular signal transduction heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction three players: the agonist-activated protein-coupled receptor (GPCR), which activates transducing protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended identification regulators and adapters such protein signaling (RGS), kinases like βARK, or GPCR-interacting arrestin are integrated into this process at different levels enable fine-tuning. Finally, atypical mechanisms regulators, together with discovery novel modulators, added new fascinating dimension transduction. heterogeneous group accessory modulators coined "activators signaling" (AGS) plays distinct roles non-canonical pathways. AGS contribute control essential functions cell development division, transport processes, secretion, autophagy movements. As such, they involved numerous biological processes crucial for diseases, diabetes mellitus, cancer, stroke, represent major health burdens. Although large number pathways has broadened spectrum communication system, their underlying mechanisms, functions, effects poorly understood. In review, we highlight discuss protein-dependent focus on inhibitory (Gi) transduction, review recent developments open questions, address potential approaches targeted pharmacological interventions.

Language: Английский

Citations

8
Constitutive activation mechanism of a class C GPCR DOI
Jin Woo Shin, Junhyeon Park, Jieun Jeong

et al.

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(4), P. 678 - 687

Published: Feb. 8, 2024

Language: Английский

Citations

7
Asymmetric mechanotransduction by hair cells of the zebrafish lateral line DOI Creative Commons
Kayla Kindig, Ruben Stepanyan, Katie S. Kindt

et al.

Current Biology, Journal Year: 2023, Volume and Issue: 33(7), P. 1295 - 1307.e3

Published: March 10, 2023

Language: Английский

Citations

15