Prominin-1 Modulates Rho/ROCK-Mediated Membrane Morphology and Calcium-Dependent Intracellular Chloride Flux

Shin

Proc. Natl. Acad. Sci. U.S.A.

et al. 2020

Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. Here we identifyProm1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program.Prom1expression is developmentally down-regulated, and the genetic deletion ofProm1in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role ofProm1in injury-induced regeneration. Elevating prominin-1 levels in cultured DRG neurons or in mice via adeno-associated virus-mediated gene delivery enhances axon regeneration in vitro and in vivo, allowing outgrowth on an inhibitory substrate.Prom1overexpression induces the consistent down-regulation of cholesterol metabolism-associated genes and a reduction in cellular cholesterol levels in a Smad pathway-dependent manner, which promotes axonal regrowth. We find that prominin-1 interacts with the type I TGF-β receptor ALK4, and that they synergistically induce phosphorylation of Smad2. These results suggest thatProm1and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.

Section: Discussionmentioning

confidence: 99%

The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling

Shin

Proc. Natl. Acad. Sci. U.S.A.

et al. 2020

“…Although we found that the expression of Edn2 and Bcl3 in the Prom1 -KO retina was induced by light stimulation, the mechanism underlying this effect remains unclear. Nevertheless, our study suggests the possibility that an imbalance in intracellular ions caused by the loss of Prom1 (given that Prom1 regulates chloride conductance activated by intracellular calcium uptake [12]) may impair the function of cytoplasmic organelles such as mitochondria and the endoplasmic reticulum, and thereby elicit a stress response. Studies to identify the transcriptional regulatory elements of Edn2 and the corresponding transcription factors and upstream signalling pathways underlying its photoactivation are warranted.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Prom1 has been detected in cilia, which are protrusive structures at the cell membrane and key signalling hubs [10], and to be essential for maximisation of Hedgehog signalling in neural stem cells [11]. We recently showed that Prom1 activates the small GTPase Rho and regulates chloride conductance triggered by intracellular calcium uptake [12].…”

Section: Introductionmentioning

confidence: 99%

Light-dependent induction ofEdn2expression and attenuation of retinal pathology by endothelin receptor antagonists inProminin-1- deficient mice

Kobayashi

Shizuka

Shirai

et al. 2020

Preprint

Self Cite

Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

“…Ttyh2 has also been shown to be involved in the formation of cell membrane extensions as Hori et al ( 2019 ) found that overexpressing ttyh2 in retinal pigment epithelium cells caused an increase in membrane extensions in those cells.…”

Section: Physiological Functions Of Tweety Proteinsmentioning

confidence: 99%

The tweety Gene Family: From Embryo to Disease

Nalamalapu

Yue

Stone

et al. 2021

Front. Mol. Neurosci.

The tweety genes encode gated chloride channels that are found in animals, plants, and even simple eukaryotes, signifying their deep evolutionary origin. In vertebrates, the tweety gene family is highly conserved and consists of three members—ttyh1, ttyh2, and ttyh3—that are important for the regulation of cell volume. While research has elucidated potential physiological functions of ttyh1 in neural stem cell maintenance, proliferation, and filopodia formation during neural development, the roles of ttyh2 and ttyh3 are less characterized, though their expression patterns during embryonic and fetal development suggest potential roles in the development of a wide range of tissues including a role in the immune system in response to pathogen-associated molecules. Additionally, members of the tweety gene family have been implicated in various pathologies including cancers, particularly pediatric brain tumors, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Here, we review the current state of research using information from published articles and open-source databases on the tweety gene family with regard to its structure, evolution, expression during development and adulthood, biochemical and cellular functions, and role in human disease. We also identify promising areas for further research to advance our understanding of this important, yet still understudied, family of genes.