The MS4A family: counting past 1, 2 and 3

Kuek, Li Eon; Leffler, Melanie; Mackay, Graham A.; Hulett, Mark D.

doi:10.1038/icb.2015.48

Cited by 105 publications

(82 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To screen for potential non-GPCR odorant receptors, the RNAseq data were filtered to identify transmembrane protein families that exhibit sufficient molecular diversity to potentially interact with a wide range of ligands. As detailed below, this screen identified the Membrane Spanning, 4-pass A ( Ms4a ) genes, which encode a class of four-transmembrane (4TM) spanning proteins that are structurally distinct from GPCRs (Eon Kuek et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

“…Previous biochemical studies relied upon clustering antibodies to trigger MS4A1-mediated calcium flux (Janas et al, 2005); this and related work suggested that the MS4As may facilitate increases in intracellular calcium by acting as co-receptors for associated ligand-binding proteins such as the B-cell receptors (Dombrowicz et al, 1998; Eon Kuek et al, 2015). However, interpreting these experiments has been difficult in light of possible gains-of-function imposed by the use of clustering reagents; here we show that small molecule ligands cause an MS4A-dependent influx of extracellular calcium, demonstrating that the MS4A molecules themselves have a receptor function.…”

Section: Discussionmentioning

confidence: 99%

“…The finding that multiple MS4As encode olfactory receptors suggests that they act as chemosensors in a range of tissues; this role may be both exteroceptive, serving to detect small molecules from the outside world, and interoceptive, as several of the ligands for MS4A proteins (e.g., oleic acid and arachidonic acid) are used as signaling molecules physiologically. Consistent with this hypothesis, members of the MS4A6/7 subfamily are expressed in microglia, neuroimmune cells responsible for sensing and responding to a variety of endogenous protein and lipid chemosignals in the mammalian brain; human MS4A8B and MS4A12 are expressed in epithelial cells at the lumenal surface of the small and large intestine, tissues that both sense dietary lipids; human MS4A8B is localized specifically in chemosensory cilia in lung cells tasked with probing the sensory environment; and MS4A5 is expressed in mammalian spermatocytes, which chemotax to oocytes (Eon Kuek et al, 2015; Koslowski et al, 2008). …”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction

Greer

Bear

Lassance

et al. 2016

Cell

127

134

View full text Add to dashboard Cite

Summary Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the “necklace” subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically-relevant ligands including pheromones and fatty acids in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction

Greer

Bear

Lassance

et al. 2016

Cell

127

134

View full text Add to dashboard Cite

show abstract

“…The membrane-spanning 4-domain subfamily A ( MS4A ) gene cluster is present on chromosome 11q12 and includes eighteen genes spanning approximately 600kb [45–47]. Multiple GWAS in European and Asian populations have implicated several genes within the MS4A cluster in AD, including MS4A4A , MS4A4E , MS4A6A , and MS4A6E [23, 48–51].…”

Section: Ad Gwas Studiesmentioning

confidence: 99%

Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk

Efthymiou

Goate

2017

Mol Neurodegeneration

439

360

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a highly heritable complex disease with no current effective prevention or treatment. The majority of drugs developed for AD focus on the amyloid cascade hypothesis, which implicates Aß plaques as a causal factor in the disease. However, it is possible that other underexplored disease-associated pathways may be more fruitful targets for drug development. Findings from gene network analyses implicate immune networks as being enriched in AD; many of the genes in these networks fall within genomic regions that contain common and rare variants that are associated with increased risk of developing AD. Of these genes, several (including CR1, SPI1, the MS4As, TREM2, ABCA7, CD33, and INPP5D) are expressed by microglia, the resident immune cells of the brain. We summarize the gene network and genetics findings that implicate that these microglial genes are involved in AD, as well as several studies that have looked at the expression and function of these genes in microglia and in the context of AD. We propose that these genes are contributing to AD in a non-Aß-dependent fashion.

show abstract

“…Members of this family were previously studied in the context of calcium signaling in the immune system, although their ligands were unknown (Eon Kuek et al, 2016). Both in vivo and in vitro analyses clearly demonstrate that the MS4As fulfill the expected criteria of odorant receptors.…”

mentioning

confidence: 92%