Non-canonical WNT5A-ROR signaling: New perspectives on an ancient developmental pathway

Snavely, Sara E. Konopelski; Srinivasan, Srisathya; Dreyer, Courtney A.; Tan, Jia; Carraway, Kermit L.; Ho, Hsin‐Yi Henry

doi:10.1016/bs.ctdb.2023.01.009

Cited by 5 publications

(4 citation statements)

References 146 publications

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“…In humans, mutations in Wnt5a, ROR2, and Dishevelled proteins cause brachydactyly type B (BDB) and Robinow syndrome. Also known as Robinow dwarfism or foetal face syndrome, it is a rare genetic disorder with significant morphogenetic abnormalities that primarily affect the development of the bones and other parts of the body 4 . Genetic experiments in mice have demonstrated that loss of Wnt5a is phenocopied by concomitant loss of ROR1 and ROR2 receptors 55 .…”

Section: Discussionmentioning

confidence: 99%

Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments in C. elegans muscles

Peysson,

Zariohi,

Gendrel

et al. 2024

Nat Commun

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Cell polarity mechanisms allow the formation of specialized membrane domains with unique protein compositions, signalling properties, and functional characteristics. By analyzing the localization of potassium channels and proteins belonging to the dystrophin-associated protein complex, we reveal the existence of distinct planar-polarized membrane compartments at the surface of C. elegans muscle cells. We find that muscle polarity is controlled by a non-canonical Wnt signalling cascade involving the ligand EGL-20/Wnt, the receptor CAM-1/Ror, and the intracellular effector DSH-1/Dishevelled. Interestingly, classical planar cell polarity proteins are not required for this process. Using time-resolved protein degradation, we demonstrate that –while it is essentially in place by the end of embryogenesis– muscle polarity is a dynamic state, requiring continued presence of DSH-1 throughout post-embryonic life. Our results reveal the unsuspected complexity of the C. elegans muscle membrane and establish a genetically tractable model system to study cellular polarity and membrane compartmentalization in vivo.

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Section: Discussionmentioning

confidence: 99%

Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments in C. elegans muscles

Peysson,

Zariohi,

Gendrel

et al. 2024

Nat Commun

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show abstract

“…In humans, mutations in Wnt5a, ROR2, and Dishevelled proteins cause brachydactyly type B (BDB) and Robinow syndrome. Also known as Robinow dwarfism or fetal face syndrome, it is a rare genetic disorder with significant morphogenetic abnormalities that primarily affect the development of the bones and other parts of the body 4 . Genetic experiments in mice have demonstrated that loss of Wnt5a is phenocopied by concomitant loss of ROR1 and ROR2 receptors 56 .…”

Section: Discussionmentioning

confidence: 99%

Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments inC. elegansmuscles

Peysson

Zariohi

Gendrel

et al. 2023

Preprint

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The plasma membrane of excitable cells is highly structured and molecular scaffolds recruit proteins to specific membrane compartments. Here, we show that potassium channels and proteins belonging to the dystrophin-associated protein complex define multiple types of planar-polarized membrane compartments at the surface of C. elegans muscle cells. Surprisingly, conserved planar cell polarity proteins are not required for this process. However, we implicate a Wnt signaling module involving the Wnt ligand EGL-20, the Wnt receptor CAM-1, and the intracellular effector DSH-1/disheveled in the formation of this cell polarity pattern. Moreover, using time-resolved and tissue-specific protein degradation, we demonstrate that muscle cell polarity is a dynamic state, requiring continued presence of DSH-1 throughout post-embryonic life. Our results reveal the intricate, highly reproducible, and entirely unsuspected complexity of the worm's sarcolemma. This novel case of planar cell polarity in a tractable genetic model organism may provide valuable insight into the molecular and cellular mechanisms that regulate cellular organization, allowing specific functions to be compartmentalized within distinct plasma membrane domains.

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“…Originally identified as orphan receptors based on sequence homology to other RTKs (hence the name R eceptor tyrosine kinase-like O rphan R eceptor), work over the past two decades has elucidated a critical role of the ROR RTK family in mediating noncanonical WNT5A signaling ( Oishi et al, 2003 ; Mikels and Nusse, 2006 ; Ho et al, 2012 ; Green et al, 2008 ). Unlike canonical WNTs, which signal through β-catenin-dependent transcription to regulate cell proliferation and tissue fate, WNT5A signals noncanonically through β-catenin-independent mechanisms to induce cytoskeletal rearrangements and tissue morphogenetic changes ( Konopelski et al, 2023 ; Moon et al, 1993 ; Veeman et al, 2003 ). The pathway is also of clinical significance, as mutations in WNT5A, the ROR family member ROR2, and the downstream signal transducers Dishevelled 1 (DVL1) and DVL3 have been reported to cause Robinow syndrome (RS), a congenital disorder characterized by systemic tissue shortening defects, including dwarfism, mesomelic limb shortening, brachydactyly, genitourinary defects, cleft palate, and other craniofacial dysmorphisms ( Person et al, 2010 ; Afzal et al, 2000 ; van Bokhoven et al, 2000 ; Bunn et al, 2015 ; White et al, 2015 ; White et al, 2016 ), and a distinct cohort of ROR2 missense mutations cause brachydactyly type B (BDB) ( Oldridge et al, 2000 ; Schwabe et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling

Griffiths,

Tan,

Wagner

et al. 2024

eLife

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The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.

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Non-canonical WNT5A-ROR signaling: New perspectives on an ancient developmental pathway

Cited by 5 publications

References 146 publications

Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments in C. elegans muscles

Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments in C. elegans muscles

Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments inC. elegansmuscles

Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling

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