The Intimate Connection Between Lipids and Hedgehog Signaling

Nguyen, Thi Diem Tien; Truong, Melissa E.; Reiter, Jeremy F.

doi:10.3389/fcell.2022.876815

Cited by 12 publications

(7 citation statements)

References 180 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite clustering with the single-treatment groups in our PCA analysis, the enrichment pro le was quite different, relating primarily to lipids. Lipids play multiple key roles in hedgehog signaling, including as ligands and as covalent modi ers of effector molecules [21,22]. The role of lipids in Gata3-mediated developmental processes is less clear.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Overlapping Targets of Shh and Gata3 during Craniofacial Development

Kar

Eberhart

2023

Preprint

View full text Add to dashboard Cite

Background Congenital birth defects are among the leading causes of infant mortality. Phenotypic variation in these defects results from a combination of genetic and environmental factors. One example of this is the modulation of palate phenotypes caused by mutation of the transcription factor Gata3 via the Sonic hedgehog (Shh) pathway. We exposed zebrafish to a subteratogenic dose of the Shh antagonist cyclopamine, and another group to both cyclopamine and gata3 knockdown. We performed RNA-seq on these zebrafish to characterize the overlap of Shh and Gata3 targets. Results We examined those genes whose expression patterns mirrored the biological effect of exacerbated misregulation. These genes were not significantly misregulated by the subteratogenic dose of ethanol but more misregulated by combinatorial disruption of Shh and Gata3 relative to Gata3 alone. Using gene-disease association discovery, we were able to refine this gene list to 11 that have published links to clinical outcomes similar to the gata3 phenotype or with craniofacial malformations. We also used weighted gene co-expression network analysis to identify a module of genes that correlate strongly with co-regulation by Shh and Gata3. This module is enriched in genes related to Wnt signaling. Conclusions We found numerous differentially expressed genes in response to cyclopamine treatment, and even more from double treatment. Most notably, we found a group of genes whose expression profile mirrored the biological effect of Shh/Gata3 interaction. Pathway analysis implicated the importance of Wnt signaling in Gata3/Shh interactions in palate development.

show abstract

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Overlapping Targets of Shh and Gata3 during Craniofacial Development

Kar

Eberhart

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Traffic of plasma membrane proteins and lipids in and out of cilia is controlled by a diffusion barrier in which PI4P (which is the predominant phosphoinositide in the ciliary shaft) and PI(4,5)P 2 (which is the predominant phosphoinositide the ciliary pocket) play an important role (Chavez et al 2015, Garcia-Gonzalo et al 2015, Nguyen et al 2022, Ojeda Naharros and Nachury 2022). Impairment of SJ1 function may disrupt the function of the diffusion barrier between the two compartments by perturbing the physiological concentration and relative ratio of PI4P and PI(4,5)P 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, or in addition, SJ1 may help control membrane protein clearing from cilia indirectly via its function in the endocytic pathway (Cremona et al 1999) as the fate of ubiquitinated proteins is to undergo endocytosis in the ciliary pocket for subsequent targeting to degradation (Nachury and Mick 2019, Shinde et al 2020). While SJ1 appears to have a primary role in the shedding of endocytic factors after endocytosis (Nguyen et al 2022), its loss-of-function, as shown by studies of nerve terminals, also results in a back-up of endocytic traffic with a partial stranding in the plasma membrane of proteins and membrane that needs to be internalized. As we have now shown that a pool of SJ1 is concentrated at the ciliary base, a special role of this protein in the endocytosis that occurs at the ciliary pocket is plausible.…”

Section: Discussionmentioning

confidence: 99%

Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons

Rafiq,

Fujise,

Rosenfeld

et al. 2023

Preprint

View full text Add to dashboard Cite

Synaptojanin-1 (SJ1) is a major neuronal-enriched PI(4,5)P24- and 5-phosphatase implicated in the shedding of endocytic factors during endocytosis. A mutation (R258Q) that impairs selectively its 4-phosphatase activity causes Parkinsonism in humans and neurological defects in mice (SJ1RQKI mice). Studies of these mice showed, besides an abnormal assembly state of endocytic factors at synapses, the presence of dystrophic nerve terminals selectively in a subset of nigro-striatal dopamine (DA)-ergic axons, suggesting a special lability of DA neurons to the impairment of SJ1 function. Here we have further investigated the impact of SJ1 on DA neurons using iPSC-derived SJ1 KO and SJ1RQKI DA neurons and their isogenic controls. In addition to the expected enhanced clustering of endocytic factors in nerve terminals, we observed in both SJ1 mutant neuronal lines increased cilia length. Further analysis of cilia of SJ1RQDA neurons revealed abnormal accumulation of the Ca2+channel Cav1.3 and of ubiquitin chains, suggesting an impaired clearing of proteins from cilia which may result from an endocytic defect at the ciliary base, where a focal concentration of SJ1 was observed. We suggest that SJ1 may contribute to the control of ciliary protein dynamics in DA neurons, with implications on cilia-mediated signaling.

show abstract

“…Different PI species bind different pleckstrin-homology (PH) domain-containing effectors and determine their subcellular localization, e.g., in the cilium (Chavez et al, 2015;Garcia-Gonzalo et al, 2015). Furthermore, other lipids, e.g., sterols, have been shown to fine tune ciliary signaling, such as Hh signaling, as reviewed by others (Nguyen et al, 2022).…”

Section: Compositional Dynamicsmentioning

confidence: 99%

Emerging principles of primary cilia dynamics in controlling tissue organization and function

Gopalakrishnan,

Feistel,

Friedrich

et al. 2023

The EMBO Journal

View full text Add to dashboard Cite

Primary cilia project from the surface of most vertebrate cells and are key in sensing extracellular signals and locally transducing this information into a cellular response. Recent findings show that primary cilia are not merely static organelles with a distinct lipid and protein composition. Instead, the function of primary cilia relies on the dynamic composition of molecules within the cilium, the context‐dependent sensing and processing of extracellular stimuli, and cycles of assembly and disassembly in a cell‐ and tissue‐specific manner. Thereby, primary cilia dynamically integrate different cellular inputs and control cell fate and function during tissue development. Here, we review the recently emerging concept of primary cilia dynamics in tissue development, organization, remodeling, and function.

show abstract

The Intimate Connection Between Lipids and Hedgehog Signaling

Cited by 12 publications

References 180 publications

WITHDRAWN: Overlapping Targets of Shh and Gata3 during Craniofacial Development

WITHDRAWN: Overlapping Targets of Shh and Gata3 during Craniofacial Development

Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons

Emerging principles of primary cilia dynamics in controlling tissue organization and function

Contact Info

Product

Resources

About