Krüppel-like transcription factors in the nervous system: Novel players in neurite outgrowth and axon regeneration

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

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EphA4 Obstructs Spinal Cord Neuron Regeneration by Promoting Excessive Activation of Astrocytes

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01046-x ◽

2021 ◽

Author(s):

Xiaogang Chen ◽

Lin Zhang ◽

Fu Hua ◽

Yu Zhuang ◽

Huan Liu ◽

...

Keyword(s):

Spinal Cord ◽

Growth Factor ◽

Neurite Outgrowth ◽

Neurotrophic Factors ◽

Cellular Localization ◽

Axon Regeneration ◽

Chondroitin Sulphate ◽

Cortical Cell ◽

Inflammatory Factors ◽

Cord Injury

AbstractStudies have found that molecular targets that regulate tissue development are also involved in regulating tissue regeneration. Erythropoietin-producing hepatocyte A4 (EphA4) not only plays a guiding role in neurite outgrowth during the development of the central nervous system (CNS) but also induces injured axon retraction and inhibits axon regeneration after spinal cord injury (SCI). EphA4 targets several ephrin ligands (including ephrin-A and ephrin-B) and is involved in cortical cell migration, axon guidance, synapse formation and astrocyte function. However, how EphA4 affects axon regeneration after SCI remains unclear. This study focuses on the effect and mechanism of EphA4-regulated astrocyte function in neuronal regeneration after SCI. Our research found that EphA4 expression increased significantly after SCI and peaked at 3 days post-injury; accordingly, we identified the cellular localization of EphA4 and ephrin-B ligands in neurons and astrocytes after SCI. EphA4 was mainly expressed on the surface of neurons, ephrin-B1 and ephrin-B3 were mainly localized on astrocytes, and ephrin-B2 was distributed on both neurons and astrocytes. To further elucidate the effect of EphA4 on astrocyte function after SCI, we detected the related cytokines secreted by astrocytes in vivo. We found that the levels of neurotrophic factors including nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) increased significantly after SCI (NGF peaked at 3 days and bFGF peaked at 7 days); the expression of laminin and fibronectin increased gradually after SCI; the expression of inflammatory factors [interleukin (IL)-1β and IL-6] increased significantly from 4 h to 7 days after SCI; and the levels of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and chondroitin sulphate proteoglycan (CSPG), the main component of glial scars, both peaked at 7 days after SCI. Using a damaged astrocyte model in vitro, we similarly found that the levels of related cytokines increased after injury. Consequently, we observed the effect of damaged astrocytes on neurite outgrowth and regeneration, and the results showed that damaged astrocytes hindered neurite outgrowth and regeneration; however, the inhibitory effect of injured astrocytes on neurite regeneration was reduced following ephrin-B receptor knockdown or inflammatory inhibition at 24 h after astrocyte injury. Our results showed that EphA4 regulates the secretion of neurotrophic factors, adhesion molecules, inflammatory factors and glial scar formation by binding with the ligand ephrin-B located on the surface of astrocytes. EphA4 affects neurite outgrowth and regeneration after SCI by regulating astrocyte function.

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Multifunctionalized Electrospun Silk Fibers Promote Axon Regeneration in the Central Nervous System

Advanced Functional Materials ◽

10.1002/adfm.201100755 ◽

2011 ◽

Vol 21 (22) ◽

pp. 4232-4242 ◽

Cited By ~ 47

Author(s):

Corinne R. Wittmer ◽

Thomas Claudepierre ◽

Michael Reber ◽

Peter Wiedemann ◽

Jonathan A. Garlick ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Axon Regeneration ◽

Silk Fibers ◽

The Central Nervous System

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Egr transcription factors in the nervous system

Neurochemistry International ◽

10.1016/s0197-0186(96)00136-2 ◽

1997 ◽

Vol 31 (4) ◽

pp. 477-510 ◽

Cited By ~ 218

Author(s):

Alison M. Beckmann ◽

Peter A. Wilce

Keyword(s):

Nervous System ◽

Transcription Factors

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mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system

eLife ◽

10.7554/elife.14908 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 48

Author(s):

Linqing Miao ◽

Liu Yang ◽

Haoliang Huang ◽

Feisi Liang ◽

Chen Ling ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Axon Regeneration ◽

Nodal Point ◽

Mtor Signaling ◽

Negative Regulator ◽

Molecular Dissection ◽

Parallel Pathways ◽

Downstream Effectors ◽

The Central Nervous System

Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.

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