LRRK2 mediates axon development by regulating Frizzled3 phosphorylation and growth cone–growth cone communication

Onishi, Keisuke; Tian, Runyi; Feng, Bo; Liu, Y.; Wang, Junkai; Li, Yinan; Zou, Yimin

doi:10.1073/pnas.1921878117

Cited by 26 publications

(26 citation statements)

References 59 publications

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“…Subsequent work showed that the function of Wnts in guiding axons along the A-P axis is conserved in a number of animal species, including rodents, chick, zebrafish, and Caenorhabditis elegans , 40 – 45 as well as the function in topographic mapping in Drosophila visual system. 46 Wnts attract axons via a non-canonical pathway, planar cell polarity pathway 40 , 47 – 51 but repel axons which express Ryk as a Wnt coreceptor. 38 , 39 For more detailed discussions about how planar cell polarity pathway mediate Wnt functions in growth cone guidance, please read another recent reviews.…”

Section: Targeting Axon Guidance To Promote Functional Recoverymentioning

confidence: 99%

Targeting axon guidance cues for neural circuit repair after spinal cord injury

Zou

2020

J Cereb Blood Flow Metab

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At least two-thirds of spinal cord injury cases are anatomically incomplete, without complete spinal cord transection, although the initial injuries cause complete loss of sensory and motor functions. The malleability of neural circuits and networks allows varied extend of functional restoration in some individuals after successful rehabilitative training. However, in most cases, the efficiency and extent are both limited and uncertain, largely due to the many obstacles of repair. The restoration of function after anatomically incomplete injury is in part made possible by the growth of new axons or new axon branches through the spared spinal cord tissue and the new synaptic connections they make, either along the areas they grow through or in the areas they terminate. This review will discuss new progress on the understanding of the role of axon guidance molecules, particularly the Wnt family proteins, in spinal cord injury and how the knowledge and tools of axon guidance can be applied to increase the potential of recovery. These strategies, combined with others, such as neuroprotection and rehabilitation, may bring new promises. The recovery strategies for anatomically incomplete spinal cord injuries are relevant and may be applicable to traumatic brain injury and stroke.

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Section: Targeting Axon Guidance To Promote Functional Recoverymentioning

confidence: 99%

Targeting axon guidance cues for neural circuit repair after spinal cord injury

Zou

2020

J Cereb Blood Flow Metab

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“…To ask whether and how Vangl2 may negatively regulate synapse numbers, we established an assay to test the intercellular PCP complex, similar to the “transcellular interaction assay” 33 . We co-transfected Frizzled3 (HA-tagged) and Celsr3 (untagged) in one dish of HEK293T cells and transfected Celsr3 (Flag-tagged) and Vangl2 in another.…”

Section: Resultsmentioning

confidence: 99%

Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling

Feng¹,

Freitas²,

Tian³

et al. 2020

Preprint

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Synapse loss is an early event in Alzheimer’s disease and is thought to be associated with amyloid pathology and caused by Amyloid β (Aβ) oligomers. Whether and how Aβ oligomers directly target signaling pathways for glutamatergic synapse maintenance is unknown. Glutamatergic synapse development is controlled by the opposing functions of Celsr3 and Vangl2, core components of the Wnt/planar cell polarity (PCP) signaling pathway, functioning directly in the synapses. Celsr3 promotes synapse formation, whereas Vangl2 inhibits synapse formation. Here we show that oligomeric Aβ binds to Celsr3 and assists Vangl2 in disassembling synapses by disrupting the intercellular Celsr3/Frizzled3-Celsr3 complex, essential for PCP signaling. Together with Vangl2, a Wnt receptor, Ryk, is also required for Aβ oligomer-induced synapse loss in a mouse model of Alzheimer’s disease, 5XFAD, where conditional Ryk knockout protected synapses and preserved cognitive function. Our study reveals a fine balance of Wnt/PCP signaling components in glutamatergic synapse maintenance and suggests that overproduced Aβ oligomers may lead to excessive synapse loss by tipping this balance. Together with previous reports that an inhibitor of Wnt/Ryk signaling, WIF1, is found reduced in Alzheimer’s disease patients, our results suggest that the imbalance of PCP signaling in these patients may contribute to synapse loss in Alzheimer’s disease and manipulating Wnt/PCP signaling may preserve synapses and cognitive function.

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“…Mice lacking Celsr exhibit impaired PCP signalling and hyperphosphorylated Fzd3 ( Wang and Nathans, 2007 ; Onishi et al, 2013 ). In addition, a recent study showed that both loss-of-function of leucine-rich repeat kinase 2 (LRRK2) and gain-of-function of mutated LRRK2 lacking kinase activity showed anterior–posterior guidance errors after midline crossing in vivo ( Onishi et al, 2020 ). Furthermore, they identified LRRK2 as a new protein which both directly phosphorylates Fzd3 on threonine 598 (T598) and indirectly promotes Dvl1-induced Fzd3 hyperphosphorylation by acting as a scaffold and recruiting other kinases ( Onishi et al, 2020 ).…”

Section: How Ptms Determine the Function Of Frizzled Receptorsmentioning

confidence: 99%

“…In addition, a recent study showed that both loss-of-function of leucine-rich repeat kinase 2 (LRRK2) and gain-of-function of mutated LRRK2 lacking kinase activity showed anterior–posterior guidance errors after midline crossing in vivo ( Onishi et al, 2020 ). Furthermore, they identified LRRK2 as a new protein which both directly phosphorylates Fzd3 on threonine 598 (T598) and indirectly promotes Dvl1-induced Fzd3 hyperphosphorylation by acting as a scaffold and recruiting other kinases ( Onishi et al, 2020 ). Overall, hypo- or non-phosphorylated Fzd3 is required for PCP signalling and for growth cone guidance in vivo ( Table 1 ; Shafer et al, 2011 ; Onishi et al, 2013 , 2020 ).…”

Section: How Ptms Determine the Function Of Frizzled Receptorsmentioning

confidence: 99%

“…Furthermore, they identified LRRK2 as a new protein which both directly phosphorylates Fzd3 on threonine 598 (T598) and indirectly promotes Dvl1-induced Fzd3 hyperphosphorylation by acting as a scaffold and recruiting other kinases ( Onishi et al, 2020 ). Overall, hypo- or non-phosphorylated Fzd3 is required for PCP signalling and for growth cone guidance in vivo ( Table 1 ; Shafer et al, 2011 ; Onishi et al, 2013 , 2020 ).…”

Section: How Ptms Determine the Function Of Frizzled Receptorsmentioning

confidence: 99%

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

Pascual-Vargas

Salinas

2021

Front. Cell Dev. Biol.

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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.

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LRRK2 mediates axon development by regulating Frizzled3 phosphorylation and growth cone–growth cone communication

Cited by 26 publications

References 59 publications

Targeting axon guidance cues for neural circuit repair after spinal cord injury

Targeting axon guidance cues for neural circuit repair after spinal cord injury

Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling

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

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