A Role for Frizzled and Their Post-Translational Modifications in the Mammalian Central Nervous System

Abstract

The Wnt pathway is a key signalling cascade that regulates the formation and function of neuronal circuits. The main receptors for Wnts are Frizzled (Fzd) that mediate diverse functions such as neurogenesis, axon guidance, dendritogenesis, synapse formation, and synaptic plasticity. These processes are crucial for the assembly of functional neuronal circuits required for diverse functions ranging from sensory and motor tasks to cognitive performance. Indeed, aberrant Wnt–Fzd signalling has been associated with synaptic defects during development and in neurodegenerative conditions such as Alzheimer’s disease. New studies suggest that the localisation and stability of Fzd receptors play a crucial role in determining Wnt function. Post-translational modifications (PTMs) of Fzd are emerging as an important mechanism that regulates these Wnt receptors. However, only phosphorylation and glycosylation have been described to modulate Fzd function in the central nervous system (CNS). In this review, we discuss the function of Fzd in neuronal circuit connectivity and how PTMs contribute to their function. We also discuss other PTMs, not yet described in the CNS, and how they might modulate the function of Fzd in neuronal connectivity. PTMs could modulate Fzd function by affecting Fzd localisation and stability at the plasma membrane resulting in local effects of Wnt signalling, a feature particularly important in polarised cells such as neurons. Our review highlights the importance of further studies into the role of PTMs on Fzd receptors in the context of neuronal connectivity.

Exosomes promote axon outgrowth by engaging the Wnt-Planar Cell Polarity pathway

“…Fzd receptors and Dvls are essential for PCP signaling, but also mediate canonical Wnt/μ-catenin signals (van Amerongen et al ., 2008). Diverse Fzd receptors have been shown to modulate events that establish neuronal morphology including axonal polarity and growth, axon guidance, dendrite morphogenesis and synaptogenesis (Pascual-Vargas & Salinas, 2021). In particular, Fzd3, 5 and 9 have been reported to be essential for axon outgrowth and guidance (Pascual-Vargas & Salinas, 2021).…”

“…Consistently, a non-redundant role for Fzd3 in mediating axon outgrowth and guidance in knockout mouse models has been described (Hua et al , 2013; Hua et al , 2014; Qu et al , 2014). The cell surface and intracellular distribution of Fzds can be modulated by post-translational modifications such as phosphorylation (Pascual-Vargas & Salinas, 2021). Moreover, in neurons, a distinctive spatiotemporal localization of Fzds in the soma, axon and growth cone during different developmental stages has been observed (Sahores et al , 2010; Varela-Nallar et al , 2012; Slater et al , 2013).…”

GPCR genes as a predictor of glioma severity and clinical outcome

“…The frizzled (FZD) family of proteins consists of 10 isoforms (FZD1–10) and many aspects of FZD signal transduction are critical for cell cycle regulation, embryonic development, cell proliferation and the development of the central nervous system. 45 – 49 Accumulating evidence shows that aberrant FZD signalling is involved in many different types of cancers and a critical role of FZD has been reported in the later stages of tumour development. 50 – 52 For example, the expression of FZD2 and FZD7 was upregulated in later-stage tumours in pancreatic adenocarcinoma; and FZE10 was highly expressed in the later stages of tumour progression in colon cancer.…”

Gene Expression Analysis of the Stress Response to Lithium, Nickel, and Zinc in Paracentrotus lividus Embryos

“…Furthermore, it is known to be involved in neurogenesis, restricting neuroectoderm to the anterior pole of the embryo with precise spatio-temporal control, involving also JNK signaling, in addition to wnt1 and wnt8 [68]. The main receptors for Wnts are Frizzled receptors that are involved in the formation and function of the neuronal circuits in mammalian central nervous system [69].…”