Ror2 is required for midgut elongation during mouse development

Abstract

The receptor tyrosine kinase Ror2 acts as a receptor for Wnt5a to mediate noncanonical Wnt signaling, and it plays essential roles in morphogenesis. Ror2 2/2 embryos exhibit phenotypes similar to, albeit generally milder than, those of Wnt5a 2/2 embryos. During mouse embryogenesis, Ror2 is expressed in various organs and regions, although little is known about its expression pattern and roles in the developing gut, while Wnt5a is expressed in the developing gut, where its absence causes abnormal phenotypes. Here, we demonstrated that Ror2 was strongly and differentially expressed in the rostral and middle midgut endoderm from embryonic day (E) 10.5 through embryonic day (E) 12.5. At E11.5, Ror2 2/2 embryos exhibited a shorter middle midgut with a larger diameter and more accumulation of epithelial cells in the middle midgut than control embryos, while the total cell numbers remained unaltered. These findings suggest that Ror2 plays important roles in midgut elongation by means of an epithelial convergent extension mechanism. Developmental Dynamics 239:941-953,

Basolateral secretion of Wnt5a in polarized epithelial cells is required for apical lumen formation

“…Our results are consistent with the findings that Ror2 is localized to the basal sides of the embryonic midgut epithelium (Yamada et al, 2010), and that LRP6 is present in the basolateral region of Xenopus outer ectodermal cells (Huang and Niehrs, 2014). Wls is essential for the trafficking of Wnts (Port and Basler, 2010), but it is not required for the apical and basolateral sorting of Wnt receptors.…”

“…However, because mesenchymal cells are the primary source of Wnt5a secretion, epithelial cells that express Wnt5a receptors at the basolateral membranes might receive Wnt5a secreted from mesenchymal cells. For example, Wnt5a and Ror2 are expressed in the mesenchyme and epithelial basal region of embryonic midgut; aberrant epithelial cell clumps, which suggest polarity loss and random orientation of cells, are observed in Ror2-knockout embryonic gut (Yamada et al, 2010). In summary, Wnt5a and its receptors are trafficked to the basolateral side of polarized epithelial cells by different mechanisms, and the basolateral secretion of Wnt5a is necessary for apical lumen formation without apoptosis.…”

Jun N-terminal kinase maintains tissue integrity during cell rearrangement in the gut

“…Recent evidence also implicates Wnt/PCP signaling in gut tube elongation, as mice lacking the Wnt/PCP ligand Wnt5a (Cervantes et al, 2009), the non-canonical Wnt/PCP receptor Ror2 (Yamada et al, 2010) or antagonists of non-canonical Wnt signaling, the Secreted-FrizzledRelated Proteins (Sfrps) (Matsuyama et al, 2009), all exhibit a dramatic shortening of the intestine.…”

Primordial germ cell migration and the Wnt signaling pathway

“…Recent publications have further implicated Wnt5a-Ror2 in various processes of mammalian cell migration including mediation of chemotactic responses, convergent extension, and cell invasiveness in the palate, gut, and osteosarcoma lines, respectively (He et al, 2008;Enomoto et al, 2009;Yamada et al, 2010). Ror2 as a biomarker and therapeutic target for metastatic cancers is also an active area of research (Morioka et al, 2009;Wright et al, 2009;Debebe and Rathmell, 2015).…”

“…Ex vivo culture data suggested a PGC-autonomous role for Ror2 in regulating migration, but broad expression of the receptor and its ligand in somatic tissues of the embryo (Yamada et al, 2010;Laird et al, 2011) raise the possibility that Ror2 function in cells of the migratory niche might influence PGC motility and development. Since the precise signaling pathways by which the Wnt5a-Ror2 pathway regulates migratory PGCs were not previously identified, questions remain about how Wnt5a regulates PGC migration without providing directional cues and whether the canonical Wnt pathway is relevant to this period of germ cell development.…”