Neurogenesis redirects β-catenin from adherens junctions to the nucleus to promote axonal growth

 If your doctor has done nothing to promote axon pathfinding, growth or sprouting, you don't have a functioning stroke doctor! Run away! You need this to reconnect  your gray matter through your white matter to the spinal cord to recover.

• axon growth (8 posts to November 2017)

• axonal sprouting (51 posts to December 2011)

• axon pathfinding (36 posts to March 2012)

Neurogenesis redirects β-catenin from adherens junctions to the nucleus to promote axonal growth

In collection: Neural development

Antonio Herrera,

Anghara Menendez,

Andrea Ochoa,

Lídia Bardia,

Julien Colombelli,

Sebastian Pons

Author and article information

Development (2023) 150 (16): dev201651.

https://doi.org/10.1242/dev.201651

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ABSTRACT

Here, we show that, in the developing spinal cord, after the early Wnt-mediated Tcf transcription activation that confers dorsal identity to neural stem cells, neurogenesis redirects β-catenin from the adherens junctions to the nucleus to stimulate Tcf-dependent transcription in a Wnt-independent manner. This new β-catenin activity regulates genes implicated in several aspects of contralateral axon growth, including axon guidance and adhesion. Using live imaging of ex-vivo chick neural tube, we showed that the nuclear accumulation of β-catenin and the rise in Tcf-dependent transcription both initiate before the dismantling of the adherens junctions and remain during the axon elongation process. Notably, we demonstrated that β-catenin activity in post-mitotic cells depends on TCF7L2 and is central to spinal commissural axon growth. Together, our results reveal Wnt-independent Tcf/β-catenin regulation of genes that control the growth and guidance of commissural axons in chick spinal cord.

2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke

Sounds useful, which stroke associations are going to fail by not pursuing human clinical trials?
http://www.sciencedirect.com/science/article/pii/S0006295213007491

acute ischemic stroke

• Chang-Ming Chern^{d, 1},
• Yea-Hwey Wang^{e, 1},
• Kuo-Tong Liou^{f, 1},
• Yu-Chang Hou^{g, h, 1},
• Chien-Chih Chen^{c, 1},
• Yuh-Chiang Shen^{a, b, e, 1, ,}

• ^a Institute of Biomedical Sciences, College of Life Science, National Chung-hsing University, Taichung, Taiwan
• ^b National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan
• ^c Departments of Biotechnology, College of Medicine and Nursing, Hung-kuang University, Taichung, Taiwan
• ^d Stroke and Neurovascular Disease Center, Section of Cerebrovascular Disease, Department of Neurology, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan
• ^e National Taipei University of Nursing and Health Science
• ^f Department of Martial Arts, Chinese Culture University, Taipei, Taiwan
• ^g Department of Chinese Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan
• ^h Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan

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Abstract

2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischaemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10∼100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.

Curcumin Loaded Nanoparticles Potently Induce Adult Neurogenesis and Reverse Cognitive Deficits in Alzheimer’s Disease Model via Canonical Wnt/β-catenin Pathway

I would think that increasing the cognitive ability of survivors would help tremendously in their recovery. How long before your doctor puts this into practice? Never? Its going to be impossible for you to get curcumin nanoparticles on your own.
http://pubs.acs.org/doi/abs/10.1021/nn405077y

Abstract

Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer’s disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self regenerative capacity. Curcumin, a neuroprotective agent has poor brain bio-availability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/β-catenin pathway, involved in regulation of neurogenesis. 

These nanoparticles caused enhanced nuclear translocation of β-catenin, decreased GSK-3β levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA mediated genetic inhibition of the Wnt pathway blocked neurogenesis stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk and GSK-3β. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway, and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self repair mechanism.

The Role and Dynamics of β-Catenin in Precondition Induced Neuroprotection after Traumatic Brain Injury

So how the hell are you going to test if this pre-conditioning  works in humans for both TBI and stroke?
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076129

Abstract

Preconditioning via heat acclimation (34°C 30 d) results in neuroprotection from traumatic brain injury due to constitutive as well as dynamic changes triggered by the trauma. Among these changes is Akt phosphorylation, which decreases apoptosis and induces HIF1α. In the present study we investigated the Akt downstream GSK3β/β -catenin pathway and focused on post injury alternations of β catenin and its impact on the cellular response in preconditioned heat acclimated mice. We found that the reduction in motor disability is accompanied with attenuation of depressive like behavior in heat acclimated mice that correlates with the GSK3β phosphorylation state. Concomitantly, a robust β catenin phosphorylation is not followed by its degradation, or by reduced nuclear accumulation. Enhanced tyrosine phosphorylation of β catenin in the injured area weakens the β catenin-N cadherin complex. Membrane β catenin is transiently reduced in heat acclimated mice and its recovery 7 days post TBI is accompanied by induction of the synaptic marker synaptophysin. We suggest a set of cellular events following traumatic brain injury in heat acclimated mice that causes β catenin to participate in cell-cell adhesion alternations rather than in Wnt signaling. These events may contribute to synaptogenesis and the improved motor and cognitive abilities seen heat acclimated mice after traumatic brain injury.

Wnt Activation of Immortalized Brain Endothelial Cells as a Tool for Generating a Standardized Model of the Blood Brain Barrier In Vitro

Another writeup on getting across the blood brain barrier. Ask your doctor and researcher which one they prefer. We are going to need this for drug delivery unless nasal wins out.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0070233

Abstract

Reproducing the characteristics and the functional responses of the blood–brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.

Lipoprotein Receptor–Related Protein-6 Protects the Brain From Ischemic Injury

This is for your doctor to decipher, it sounds like a possibility for stopping the neuronal cascade of death. Ask for a protocol from this in the first week.
http://stroke.ahajournals.org/content/early/2013/06/06/STROKEAHA.113.001320.abstract

Abstract

Background and Purpose—Loss-of-function mutations of the lipoprotein receptor–related protein-6 (LRP6), a coreceptor in the Wingless-related integration site-β−catenin prosurvival pathway, have been implicated in myocardial ischemia and neurodegeneration. However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6^+/− mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia.

Methods—Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery. Motor deficits and infarct volume were assessed 3 days later. Glycogen-synthase-kinase-3β (GSK-3β) phosphorylation was examined by Western blotting with phosphospecific antibodies, and the mitochondrial membrane potential changes induced by Ca²⁺ were also assessed.

Results—LRP6^+/− mice have larger stroke and more severe motor deficits, effects that were independent of intraischemic cerebral blood flow, vascular factors, or cytosolic β-catenin levels. Rather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3β, a kinase involved in proinflammatory signaling and mitochondrial dysfunction. Accordingly, postischemic inflammatory gene expression was enhanced in LRP6^+/− mice. Furthermore, the association of mitochondria with activated GSK-3β was increased in LRP6^+/− mice, resulting in a reduction in the Ca²⁺ handling ability of mitochondria. The mitochondrial dysfunction was reversed by pharmacological inhibition of GSK-3β.

Conclusions—LRP6 activates an endogenous neuroprotective pathway that acts independently of β-catenin by controlling GSK-3β activity and preventing its deleterious mitochondrial and proinflammatory effects. The findings raise the possibility that emerging treatment strategies for diseases attributable to LRP6 loss-of-function mutations could also lead to new therapeutic avenues for ischemic stroke.

Up-regulation of the canonical Wnt-3 A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia

More hedgehogs, get your researcher involved.
http://www.sciencedirect.com/science/article/pii/S0014299913002203

Abstract

In experimental cerebral ischemia, melanocortin MC₄ receptor agonists induce neuroprotection and neurogenesis with subsequent long-lasting functional recovery. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis. Gerbils were subjected to transient global cerebral ischemia, then they were treated every 12 h, and until sacrifice, with 5-bromo-2’-deoxyuridine (BrdU; to label proliferating cells), and the melanocortin analog [Nle⁴,D-Phe⁷]α-melanocyte-stimulating hormone (NDP-α-MSH) or saline. NDP-α-MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3 A, β-catenin, Sonic hedgehog (Shh), Zif268, interleukin-10 (IL-10) and doublecortin (DCX), as detected at days 3, 6 and 10 after the ischemic insult. Further, an elevated number of BrdU immunoreactive cells was found at days 3 and 10, and an improved histological picture with reduced neuronal loss at day 10, associated with learning and memory recovery. Pharmacological blockade of the Wnt-3 A/β-catenin and Shh pathways, as well as of melanocortin MC₄ receptors, prevented all effects of NDP-α-MSH. These data indicate that, in experimental brain ischemia, treatment with melanocortins acting at MC₄ receptors induces neural stem/progenitor cell proliferation in the DG by promptly and effectively triggering the canonical Wnt-3 A/β-catenin and Shh signaling pathways. Activation of these pathways is associated with up-regulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly towards a neuronal fate, as indicated by the increase in DCX positive cells.

Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling

Ask your doctor how you can use this in your rehab.
http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3212.html

Abstract

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Neurogenesis in the adult hippocampus involves activation of quiescent neural stem cells (NSCs) to yield transiently amplifying NSCs, progenitors, and, ultimately, neurons that affect learning and memory. This process is tightly controlled by microenvironmental cues, although a few endogenous factors are known to regulate neuronal differentiation. Astrocytes have been implicated, but their role in juxtacrine (that is, cell-cell contact dependent) signaling in NSC niches has not been investigated. We found that ephrin-B2 presented from rodent hippocampal astrocytes regulated neurogenesis in vivo. Furthermore, clonal analysis in NSC fate-mapping studies revealed a previously unknown role for ephrin-B2 in instructing neuronal differentiation. In addition, ephrin-B2 signaling, transduced by EphB4 receptors on NSCs, activated β-catenin in vitro and in vivo independently of Wnt signaling and upregulated proneural transcription factors. Ephrin-B2⁺ astrocytes therefore promote neuronal differentiation of adult NSCs through juxtacrine signaling, findings that advance our understanding of adult neurogenesis and may have future regenerative medicine implications.