The Ror-Family Receptors in Development, Tissue Regeneration and Age-Related Disease

Endo, Mitsuharu; Kamizaki, Koki; Minami, Yasuhiro

doi:10.3389/fcell.2022.891763

Cited by 16 publications

(14 citation statements)

References 130 publications

(151 reference statements)

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“…Interestingly, both receptors share an evolutionary conserved FZD domain in the ECD ( Yan et al, 2014 ). ROR1 and its closely related paralog ROR2 are receptors for Wnt5a and other Wnts in the planar cell polarity pathway ( Endo et al, 2022 ; Green et al, 2014 ; Minami et al, 2010 ). MFRP is Type II transmembrane protein with an extracellular FZD domain.…”

Section: Resultsmentioning

confidence: 99%

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Siepe

Henneberg

Wilson

et al. 2022

eLife

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Secreted proteins, which include cytokines, hormones and growth factors, are extracellular ligands that control key signaling pathways mediating cell-cell communication within and between tissues and organs. Many drugs target secreted ligands and their cell-surface receptors. Still, there are hundreds of secreted human proteins that either have no identified receptors ('orphans') and are likely to act through cell surface receptors that have not yet been characterized. Discovery of secreted ligand-receptor interactions by high-throughput screening has been problematic, because the most commonly used high-throughput methods for protein-protein interaction (PPI) screening do not work well for extracellular interactions. Cell-based screening is a promising technology for definition of new ligand-receptor interactions, because multimerized ligands can enrich for cells expressing low affinity cell-surface receptors, and such methods do not require purification of receptor extracellular domains. Here, we present a proteo-genomic cell-based CRISPR activation (CRISPRa) enrichment screening platform employing customized pooled cell surface receptor sgRNA libraries in combination with a magnetic bead selection-based enrichment workflow for rapid, parallel ligand-receptor deorphanization. We curated 80 potentially high value orphan secreted proteins and ultimately screened 20 secreted ligands against two cell sgRNA libraries with targeted expression of all single-pass (TM1) or multi-pass (TM2+) receptors by CRISPRa. We identified previously unknown interactions in 12 of these screens, and validated several of them using surface plasmon resonance and/or cell binding. The newly deorphanized ligands include three receptor tyrosine phosphatase (RPTP) ligands and a chemokine like protein that binds to killer cell inhibitory receptors (KIR's). These new interactions provide a resource for future investigations of interactions between the human secreted and membrane proteomes.

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Section: Resultsmentioning

confidence: 99%

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Siepe

Henneberg

Wilson

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…Intestingly, both receptors share a evolutionary conserved Frizzled domain in the ECD (Yan et al, 2014). ROR1 and its closely related paralog ROR2 are receptors for Wnt5a and other Wnts in the planar cell polarity (PCP) pathway (Endo et al, 2022; Green et al, 2014; Minami et al, 2010). MFRP (Membrane frizzled-related protein) is type II transmembrane protein with an extracellular FZD domain.…”

Section: Resultsmentioning

confidence: 99%

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Siepe

Henneberg

Wilson

et al. 2022

Preprint

View full text Add to dashboard Cite

Secreted proteins, which include cytokines, hormones and growth factors, are extracellular ligands that control key signaling pathways mediating cell-cell communication within and between tissues and organs. Many drugs target secreted ligands and their cell-surface receptors. Still, there are hundreds of secreted human proteins that either have no identified receptors ('orphans') and are likely to act through cell surface receptors that have not yet been characterized. Discovery of secreted ligand-receptor interactions by high-throughput screening has been problematic, because the most commonly used high-throughput methods for protein-protein interaction (PPI) screening do not work well for extracellular interactions. Cell-based screening is a promising technology for definition of new ligand-receptor interactions, because multimerized ligands can enrich for cells expressing low affinity cell-surface receptors, and such methods do not require purification of receptor extracellular domains. Here, we present a proteo-genomic cell-based CRISPR activation (CRISPRa) enrichment screening platform employing customized pooled cell surface receptor sgRNA libraries in combination with a magnetic bead selection-based enrichment workflow for rapid, parallel ligand-receptor deorphanization. We curated 80 potentially high value orphan secreted proteins and ultimately screened 20 secreted ligands against two cell libraries with targeted expression of all single-pass (TM1) or multi-pass (TM2+) receptors by CRISPRa. We identified previously unknown interactions in 12 of these screens, and validated several of them using surface plasmon resonance and/or cell binding. The newly deorphanized ligands include three receptor tyrosine phosphatase ligands and a chemokine like protein that binds to killer cell inhibitory receptors. These new interactions provide a resource for future investigations of interactions between the human secreted and membrane proteomes.

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“…Noncanonical WNT signals are less well studied than canonical signals. Wnt5a is one of the typical noncanonical WNT ligands and can bind to its receptor Ror2, which belongs to the family of tyrosine-protein kinase transmembrane receptors (83,84). Interestingly, deletion of Ror2 in the root progenitor cells of the mouse molar leads to a reduction in root length, suggesting noncanonical WNT signaling plays a vital role in tooth development (85).…”

Section: Wnt Signalingmentioning

confidence: 99%

Rodent incisor as a model to study mesenchymal stem cells in tissue homeostasis and repair

et al. 2022

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The homeostasis of adult tissues, such as skin, hair, blood, and bone, requires continuous generation of differentiated progeny of stem cells. The rodent incisor undergoes constant renewal and can provide an extraordinary model for studying stem cells and their progeny in adult tissue homeostasis, cell differentiation and injury-induced regeneration. Meanwhile, cellular heterogeneity in the mouse incisor also provides an opportunity to study cell-cell communication between different cell types, including interactions between stem cells and their niche environment. More importantly, the molecular and cellular regulatory mechanisms revealed by the mouse incisor have broad implications for other organs. Here we review recent findings and advances using the mouse incisor as a model, including perspectives on the heterogeneity of cells in the mesenchyme, the niche environment, and signaling networks that regulate stem cell behavior. The progress from this field will not only expand the knowledge of stem cells and organogenesis, but also bridge a gap between animal models and tissue regeneration.

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The Ror-Family Receptors in Development, Tissue Regeneration and Age-Related Disease

Cited by 16 publications

References 130 publications

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Rodent incisor as a model to study mesenchymal stem cells in tissue homeostasis and repair

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