A novel Wnt5a‐Frizzled4 signaling pathway mediates activity‐independent dendrite morphogenesis via the distal PDZ motif of Frizzled 4

Abstract

The morphology of the dendritic tree is critical to neuronal function and neural circuit wiring. Several Wnt family members have been demonstrated to play important roles in dendrite development. However, the Wnt receptors responsible for mediating this process remain largely elusive. Using primary hippocampal neuronal cultures as a model system, we report that Frizzled4 (Fzd4), a member of the Fzd family of Wnt receptors, specifically signals downstream of Wnt5a to promote dendrite branching and growth. Interestingly, the less conserved distal PDZ binding motif of Fzd4, and not its conserved proximal Dvl-interacting PDZ motif, is required for mediating this effect. We further showed that Dvl signaled parallel to and independent of Fzd4 in promoting dendrite growth. Unlike most previously described pathways, Wnt5a/Fzd4 signaling promoted dendrite development in an activity-independent and autocrine fashion. Together, these results provide the first identification of a Wnt receptor for regulating dendrite development in the mammalian system, and demonstrate a novel function of the distal PDZ motif of Fzd4 in dendrite morphogenesis, thereby expanding our knowledge of the complex roles of Wnt signaling in neural development.

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

“…S1 F-J). These results show that Wnt5a is dispensable for establishing dendritic arbors and for spine formation in CA1 pyramidal neurons in vivo, contrary to published reports that Wnt5a promotes neuronal morphogenesis in cultured hippocampal neurons (15,18,19,32).…”

“…Previous studies have implicated Wnt5a in regulating developmental axon and dendrite outgrowth and synapse formation in cultured hippocampal neurons (15)(16)(17)(18)(19)(20). Here, we report that Wnt5a deletion does not compromise hippocampal development or maturation in vivo, but results in striking adultonset defects in dendrite arborization, lengths, and spine densities in CA1 hippocampal pyramidal neurons that manifest after 4 mo of age in mice.…”

“…These results were surprising in the context of reported developmental functions for Wnt5a in cultured hippocampal neurons, and in embryonic processes in other brain regions (15,18,19). In hippocampal neurons, several signaling pathways have been shown to influence dendrite morphogenesis, maturation, and stability in vitro and in vivo (1,6,69).…”

WNT5A and Its Receptors in the Bone-Cancer Dialogue

“…Yes (10,105,106) No Prostate cancer (76,77) ; melanoma (91) ; non-small cell lung cancer (107) ; ovarian cancer (108) …”

Development of a vascularized, induced pluripotent stem cell-derived liver-tissue mimic for therapeutic applications.

“…Wnt5a has been shown to interact with a number of receptors, including Frizzled-4 393 , -5 378,388,394 , and ROR2 395,396 . Similar to our Wnt PCR, we tested hSVF cDNA from day 1, 3, and 5 cultures for expression of these receptors.…”