Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA

Javier-Torrent, Míriam; Marco, Sergi; Rocandio, Daniel; Pons-Vizcarra, Maria; Janes, Peter W.; Lackmann, Martin; Egea, Joaquim; Saura, Carlos A.

doi:10.7554/elife.43646

Cited by 18 publications

(20 citation statements)

References 65 publications

(97 reference statements)

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“…NMIIA also mediates growth cone collapse and neurite retraction in response to repulsive guidance molecule (RGMa) [82]. In the case of ephrin-A5, a non-permissive molecule, by binding to EphA3 it triggers the activation of RhoA/ROCK activating NMIIA and ultimately leading to axon repulsion [92]. This context-specific role of NMIIA/B response to different guidance cues is certainly the subject of the intricate regulation, balance and spatial distribution of both NMII isoforms.…”

Section: Nmiia and Nmiib Play Central Roles In Axon Guidancementioning

confidence: 99%

Non-Muscle Myosin II in Axonal Cell Biology: From the Growth Cone to the Axon Initial Segment

Costa¹,

Sousa²

2020

Cells

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By binding to actin filaments, non-muscle myosin II (NMII) generates actomyosin networks that hold unique contractile properties. Their dynamic nature is essential for neuronal biology including the establishment of polarity, growth cone formation and motility, axon growth during development (and axon regeneration in the adult), radial and longitudinal axonal tension, and synapse formation and function. In this review, we discuss the current knowledge on the spatial distribution and function of the actomyosin cytoskeleton in different axonal compartments. We highlight some of the apparent contradictions and open questions in the field, including the role of NMII in the regulation of axon growth and regeneration, the possibility that NMII structural arrangement along the axon shaft may control both radial and longitudinal contractility, and the mechanism and functional purpose underlying NMII enrichment in the axon initial segment. With the advances in live cell imaging and super resolution microscopy, it is expected that in the near future the spatial distribution of NMII in the axon, and the mechanisms by which it participates in axonal biology will be further untangled.

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Section: Nmiia and Nmiib Play Central Roles In Axon Guidancementioning

confidence: 99%

Non-Muscle Myosin II in Axonal Cell Biology: From the Growth Cone to the Axon Initial Segment

Costa¹,

Sousa²

2020

Cells

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“…Which are the roles of NMIIs in axon growth? Genetic and pharmacological studies have shown a critical role, and sometimes even opposite functions, of NMII isoforms in neuronal adhesion and growth cone dynamics [ 28 , 29 , 59 , 60 , 61 , 62 , 63 ] ( Figure 2 ). NMIIA is a downstream effector of the Rho GTPase signaling pathway during neurite retraction [ 64 ].…”

Section: Functions Of Non-muscle Myosin II In the Nervous Systemmentioning

confidence: 99%

“…NMIIA is a downstream effector of the Rho GTPase signaling pathway during neurite retraction [ 64 ]. Disruption of NMIIA activity induces a rearrangement of the actin cytoskeleton and loss of focal contacts that leads to an increase of axon length in DRG neurons [ 28 , 63 , 65 , 66 ], whereas overexpression of a non-phosphorylable NMIIA mutant that promotes myosin assembly impairs axon elongation in hippocampal neurons [ 59 ]. By contrast, NMIIB facilitates neurite and axon growth, as revealed by decreased neurite outgrowth by NMIIB knockdown in neuroblastoma cells [ 63 , 65 ], and impaired axonal outgrowth and growth cone morphology in Myh10 knockout mice [ 55 ].…”

Section: Functions Of Non-muscle Myosin II In the Nervous Systemmentioning

confidence: 99%

“…Since many guidance cues mediate axon retraction in different neuronal subtypes, it is possible that they may modulate the strength of the response that leads to the activation of Rho signaling that in turn modulates NMII activity ( Figure 3 ). Some evidence that supports this model includes: (i) slit and netrin-1 mediate growth cone collapse in cranial motor neurons [ 70 ], (ii) ephrin-A5 induces growth cone collapse and axon retraction in hippocampal and retinal ganglion neurons [ 59 , 71 , 72 ]; (iii) the nerve growth factor (NGF) controls growth cone polarity and guidance in forebrain neurons [ 53 ]; and (iv) all these functions rely on the activation of RhoA and MLCK signaling. These studies also support the idea that guidance cues may contribute differentially to neuronal polarization depending on the neuronal type.…”

Section: Functions Of Non-muscle Myosin II In the Nervous Systemmentioning

confidence: 99%

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Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration

Javier-Torrent

Saura

2020

Cells

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Myosins are motor proteins that use chemical energy to produce mechanical forces driving actin cytoskeletal dynamics. In the brain, the conventional non-muscle myosin II (NMII) regulates actin filament cytoskeletal assembly and contractile forces during structural remodeling of axons and dendrites, contributing to morphology, polarization, and migration of neurons during brain development. NMII isoforms also participate in neurotransmission and synaptic plasticity by driving actin cytoskeletal dynamics during synaptic vesicle release and retrieval, and formation, maturation, and remodeling of dendritic spines. NMIIs are expressed differentially in cerebral non-neuronal cells, such as microglia, astrocytes, and endothelial cells, wherein they play key functions in inflammation, myelination, and repair. Besides major efforts to understand the physiological functions and regulatory mechanisms of NMIIs in the nervous system, their contributions to brain pathologies are still largely unclear. Nonetheless, genetic mutations or deregulation of NMII and its regulatory effectors are linked to autism, schizophrenia, intellectual disability, and neurodegeneration, indicating non-conventional roles of NMIIs in cellular mechanisms underlying neurodevelopmental and neurodegenerative disorders. Here, we summarize the emerging biological roles of NMIIs in the brain, and discuss how actomyosin signaling contributes to dysfunction of neurons and glial cells in the context of neurological disorders. This knowledge is relevant for a deep understanding of NMIIs on the pathogenesis and therapeutics of neuropsychiatric and neurodegenerative diseases.

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“…Presenilin is the catalytic subunit of γ-secretase and these mutations alter the cleavage of the Amyloid Precursor Protein (APP), which is at least partially responsible for AD pathology (35), though this has remained controversial (37). Despite clear clinical relevance, the biological functions of Presenilin and γ-secretase remain incompletely understood among roles in cell-cell signaling (33), axon guidance (38), vesicle cycling (39,40), and neuronal development (41)(42)(43). Our identification of Psn and Nct in a genetic screen raised the intriguing possibility that γ-secretase could promote postsynaptic maturation via the mechanism of Fz2 cleavage.…”

Section: An In Vivo Screen To Identify Proteases Involved In Synapticmentioning

confidence: 99%

γ-secretase promotes postsynaptic maturation through the cleavage of a Wnt receptor

Restrepo

DePew

Moese

et al. 2020

Preprint

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An emerging feature of neurodegenerative disease is synaptic dysfunction and loss, leading to the suggestion that mechanisms required for synaptic maturation may be linked to disease. Synaptic maturation requires the transmission of signals between nascent synaptic sites and the nucleus, but how these signals are generated is not well understood. We posit that proteolytic cleavage of receptors, which enables their translocation to the nucleus, may be a shared molecular mechanism between the events that promote synaptic maturation and those linked to later-onset disorders of the nervous system, including neurodegenerative disease. Here we show during synaptic development, that cleavage of synaptic maturation molecules requires γ-secretase, a protein complex linked to Alzheimer’s Disease, a devastating neurodegenerative condition, is required for postsynaptic maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to appropriately recruit postsynaptic scaffolding and cytoskeletal proteins, and mutant larvae display behavioral deficits. At the NMJ, γ-secretase promotes synaptic maturation through the cleavage of the Wnt receptor Fz2, and the subsequent entry of its C-terminus into the nucleus. A developmental synaptic role for γ-secretase is also conserved in both the Drosophila central nervous system and mammalian cortical neuron dendrites. Finally, we found that similar maturation defects are evident in fly models for ALS, Alzheimer’s, Huntington’s, and Parkinson’s Diseases. The previously unknown, but conserved, role for γ-secretase coupled with its well-known role in neurodegenerative disease suggest that neurodevelopmental defects may be common to diverse neurodegenerative disease models.

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Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA

Cited by 18 publications

References 65 publications

Non-Muscle Myosin II in Axonal Cell Biology: From the Growth Cone to the Axon Initial Segment

Non-Muscle Myosin II in Axonal Cell Biology: From the Growth Cone to the Axon Initial Segment

Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration

γ-secretase promotes postsynaptic maturation through the cleavage of a Wnt receptor

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