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

Abstract

The Ror-family proteins, Ror1 and Ror2, act as receptors or co-receptors for Wnt5a and its related Wnt proteins to activate non-canonical Wnt signaling. Ror1 and/or Ror2-mediated signaling plays essential roles in regulating cell polarity, migration, proliferation and differentiation during developmental morphogenesis, tissue-/organo-genesis and regeneration of adult tissues following injury. Ror1 and Ror2 are expressed abundantly in developing tissues in an overlapping, yet distinct manner, and their expression in adult tissues is restricted to specific cell types such as tissue stem/progenitor cells. Expression levels of Ror1 and/or Ror2 in the adult tissues are increased following injury, thereby promoting regeneration or repair of these injured tissues. On the other hand, disruption of Wnt5a-Ror2 signaling is implicated in senescence of tissue stem/progenitor cells that is related to the impaired regeneration capacity of aged tissues. In fact, Ror1 and Ror2 are implicated in age-related diseases, including tissue fibrosis, atherosclerosis (or arteriosclerosis), neurodegenerative diseases, and cancers. In these diseases, enhanced and/or sustained (chronic) expression of Ror1 and/or Ror2 is observed, and they might contribute to the progression of these diseases through Wnt5a-dependent and -independent manners. In this article, we overview recent advances in our understanding of the roles of Ror1 and Ror2-mediated signaling in the development, tissue regeneration and age-related diseases, and discuss their potential to be therapeutic targets for chronic inflammatory diseases and cancers.

Keywords: cancers; cell polarity; cellular senescence; inflammation; migration; non-canonical wnt signaling; proliferation; stem/progenitor cells.

FIGURE 1

Schematic representation of the Ror-family receptors (Ror1/Ror2)-mediated signaling, implicated in the regulation of Wnt5a-induced cell polarity, migration, proliferation, and survival. (A) The Ror-family receptors induce filopodia formation and JNK activation via the interaction with FLNa, leading to the regulation of cell polarity and migration. Wnt5a-Ror signaling can also induce activation of c-Src and Dvl, leading to the activation of JNK. c-Src and GSK3, respectively, phosphorylate the Ror-family receptors on their tyrosine and serine/threonine residues, both of which are required for Wnt5a-induced cell polarity and migration. (B) Wnt5a-Ror signaling can activate PI3K-Akt pathway presumably via CKIε associated with Ror1/Ror2, which in turn promotes cell proliferation and survival. c-Src, activated by Wnt5a-Ror signaling, can also induce activation of Akt, thereby contributing to cell proliferation and survival.

FIGURE 2

| Possible roles of the Ror-family receptors up-regulated by injury and aging in the tissue repair/regeneration and the age-related diseases. (A) Expression levels of Ror1 and/or Ror2 are increased transiently in somewhat restricted (specific) cells, including stem/progenitor cells and astrocytes, within the damaged tissues following injury, via environmental cues including inflammatory cytokines and growth factors. Up-regulated Ror1/Ror2 in turn contribute to the promotion of tissue repair or regeneration. Aging can mediate decreased expression of the Ror-family receptors in the tissue stem/progenitor cells, resulting in the dysfunction of these tissue stem/progenitor cells in regulating tissue repair or regeneration. (B) Sustained expression of Ror1 and/or Ror2 are induced in various types of cells under chronic inflammation caused by aging, thereby contributing to the development or progression of the age-related diseases, including fibrosis, arteriosclerosis, neurodegenerative diseases, and various cancers.