Spatial ciliary signaling regulates the dorsal/ventral regionalization of human brain organoids DOI
Issei S. Shimada, A Goto, Yutaka Hashimoto

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 20, 2024

Abstract Regionalization of the brain is a fundamental question in human developmental biology. Primary cilia are known for critical organelle dorsal/ventral fate formation mice, but little about how signaling primary regulate regionalization brain. Here, we found that function using organoids derived from induced pluripotent stem (iPS) cells. Deletion ciliary GTPase, ARL13B , partially ventralized neural cells dorsal cortical organoids, despite guided organoid differentiation protocol. Mechanistically, knockout (KO) decreased localization GPR161, negative regulator SHH and increased SONIC HEDGEHOG (SHH) signaling. GPR161 deletion also mediated by GLI3 repressor formation. Pharmacological treatment to increase cAMP levels rescued KO organoids. Importantly, elevating amount optogenetics restored generation These data indicate spatial signaling, ARL13B-GPR161-cAMP axis cilia,

Language: Английский

Emerging mechanistic understanding of cilia function in cellular signalling DOI
Keren I. Hilgendorf, Benjamin R. Myers, Jeremy F. Reiter

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(7), P. 555 - 573

Published: Feb. 16, 2024

Language: Английский

Citations

43
GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade DOI Creative Commons
Madison F. Walker, Jingyi Zhang,

William Steiner

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(8), P. e3002685 - e3002685

Published: Aug. 13, 2024

During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding protein kinase A catalytic subunit (PKA-C) physically blocking its enzymatic activity. Here, we show that GPCR 2 (GRK2) orchestrates this process during endogenous mouse zebrafish Hh pathway activation primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from ciliary base to shaft, triggering phosphorylation PKA-C interaction. Reconstitution studies reveal enables active bind directly. Lastly, SMO-GRK2-PKA underlies a range of cellular vivo models. Thus, ensuing inactivation are critical initiating events for intracellular steps signaling. More broadly, our study suggests an expanded role GRKs enabling direct interactions diverse effectors.

Language: Английский

Citations

5
Integration of ATAC-seq and RNA-seq reveals signal regulation during post-molt and inter-molt stages in muscle of Eriocheir sinensis DOI Creative Commons
Bin Wang, Jinɡjinɡ Li, Mingzhi Zhang

et al.

Frontiers in Marine Science, Journal Year: 2025, Volume and Issue: 11

Published: Jan. 21, 2025

Introduction The molting processes are crucial for the survival and development of crustaceans. Eriocheir sinensis demonstrates representative discontinuous growth during molting, while muscle is most obvious tissue exhibiting this property. However, signal regulation mechanisms involved in remain unexplored. Methods In work, a comprehensive analysis gene expressions E. between post-molt inter-molt stages were performed by integrating ATAC-seq RNA-seq techniques. Results integration identified 446 up-regulated 21 down-regulated genes two stages. GO enrichment revealed that largely associated with protein phosphorylation phosphorus metabolism, mainly DNA transcription, cell adhesion, G protein-coupled receptor (GPCR) signaling pathway. all enriched pathways, GPCR pathway includes differentially expressed (8 genes), which underlines its importance transduction from stage to stage. Further structure RT-qPCR validation confirmed five related process, four ( GRM7, FMRFaR, mth2, gpr161 ) active one moody functions Discussion These findings highlight key regulatory proteins pathways also offer foundational data studying

Language: Английский

Citations

0
GPR137-RAB8A activation promotes ovarian cancer development via the Hedgehog pathway DOI Creative Commons
Chao Tang, Lin Li,

Chongying Zhu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Jan. 24, 2025

Language: Английский

Citations

0
Tonic ubiquitination of the central body weight regulator melanocortin receptor 4 (MC4R) promotes its constitutive exit from cilia DOI Creative Commons

Irene Ojeda-Naharros,

Tirthasree Das,

Rondinelle Ribeiro Castro

et al.

PLoS Biology, Journal Year: 2025, Volume and Issue: 23(2), P. e3003025 - e3003025

Published: Feb. 3, 2025

The G protein-coupled receptor (GPCR) melanocortin 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R unusual among GPCRs in that its activity regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and antagonist/inverse AgRP. Paradoxically, while localizes functions at cilium hypothalamic neurons, ciliary levels are very low under unrestricted feeding conditions. Here, we find constitutive responsible for continuous depletion from cilia inhibition MC4R’s via AgRP leads to a robust accumulation cilia. Ciliary targeting mediated partner MRAP2 exit relies on sensor activation β-arrestin, ubiquitination, BBSome trafficking complex. Thus, exits conventional mechanisms, it only accumulates when suppressed

Language: Английский

Citations

0
The Intersections between Neuroscience and Medulloblastoma DOI
Yafei Wang, Ying Yu, Jiahua Yu

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217660 - 217660

Published: March 1, 2025

Language: Английский

Citations

0
Cryo-EM as a tool for illuminating activation mechanisms of human class A orphan GPCRs DOI Creative Commons
Isabella C. Russell,

Dongju Lee,

Denise Wootten

et al.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100056 - 100056

Published: April 1, 2025

Language: Английский

Citations

0
Shifting our perspective on orphan G protein-coupled receptors DOI
Nicola J. Smith, Fiona Murray

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(4), P. 582 - 583

Published: April 1, 2024

Language: Английский

Citations

3
Molecular and structural perspectives on protein trafficking to the primary cilium membrane DOI Creative Commons
Vivek Reddy Palicharla, Saikat Mukhopadhyay

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(3), P. 1473 - 1487

Published: June 12, 2024

The primary cilium is a dynamic subcellular compartment templated from the mother centriole or basal body. Cilia are solitary and tiny, but remarkably consequential in cellular pathways regulating proliferation, differentiation, maintenance. Multiple transmembrane proteins such as G-protein-coupled receptors, channels, enzymes, membrane-associated lipidated enriched ciliary membrane. precise regulation of membrane content essential for effective signal transduction maintenance tissue homeostasis. Surprisingly, few conserved molecular factors, intraflagellar transport complex A tubby family adapter protein TULP3, mediate most cargoes into cilia. Recent advances cryogenic electron microscopy provide fundamental insights these players. Here, we review players mediating cargo delivery through lens structural biology. These mechanistic framework understanding disease variants ciliopathies, enable manipulation cilia-mediated pathways, platform development targeted therapeutics.

Language: Английский

Citations

3
Structural basis of frizzled 7 activation and allosteric regulation DOI Creative Commons
Julien Bous, Julia Kinsolving, Lukas Grätz

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 28, 2024

Frizzleds (ten paralogs: FZD

Language: Английский

Citations

2