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I was reading in a book that in the process of neurogenesis - when new neurons are born - neurons compete for survival. Or in other words they have to make themselves useful to the brain otherwise they die and become processed as brain food.
To what extent is this real and how often does this happen?
i think that in the book I was reading it the author mentions it happening in early life, but I'm not entirely sure.
Would be great to know.
It's definitely real ;)
Depending on your previous knowledge, this review from 1987 might be a good starting point. http://science.sciencemag.org/content/237/4819/1154.long
To give you an idea of recent developments this article is an easy read. Be sure to browse the references. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612357/
Animal models for neurodegenerative disorders
Severe spinal muscular atrophy mice (mSMN −/− SMN2 +/+ )
SMN knockout mice (mSMN −/− mice) were generated by the conventional gene targeting method to disrupt exon 2 of the mouse SMN gene by inserting the Escherichia coli LacZ gene ( Schrank et al., 1997 ). SMN knockout mice (mSMN −/− ) die at the early embryonic stage, while heterozygote mSMN +/− mice do not show any detectable abnormalities. To rescue severe phenotype SMN knockout mice, the entire human SMN2 gene including its promoter with a length of 35.5 kb was injected into embryos to generate SMN2 transgenic mice ( Monani et al., 2000 ). Four founders were obtained. Two lines with 1 or 8 copies of SMN2 genes were bred to C57BL/6J mSMN +/− mice to produce mSMN +/− SMN2 progeny. The introduction of one copy of SMN2 gene rescued embryonic lethality from mSMN deficiency, resulting in severe SMA phenotype ( Fig. 3.1E ). The mSMN −/− SMN2 +/+ mice (called as severe SMA mice) can survive for 8 days, but most of them die between 4 and 6 days. SMN knockout mice carrying higher copy number SMN2 transgene did not show any obvious phenotypes, indicating that the introduction of eight copies of SMN2 is sufficient to rescue the SMA phenotype.
A model for sealing plasmalemmal damage in neurons and other eukaryotic cells
Plasmalemmal repair is necessary for survival of damaged eukaryotic cells. Ca(2+) influx through plasmalemmal disruptions activates calpain, vesicle accumulation at lesion sites, and membrane fusion proteins Ca(2+) influx also initiates competing apoptotic pathways. Using the formation of a dye barrier (seal) to assess plasmalemmal repair, we now report that B104 hippocampal cells with neurites transected nearer (<50 μm) to the soma seal at a lower frequency and slower rate compared to cells with neurites transected farther (>50 μm) from the soma. Analogs of cAMP, including protein kinase A (PKA)-specific and Epac-specific cAMP, each increase the frequency and rate of sealing and can even initiate sealing in the absence of Ca(2+) influx at both transection distances. Furthermore, Epac activates a cAMP-dependent, PKA-independent, pathway involved in plasmalemmal sealing. The frequency and rate of plasmalemmal sealing are decreased by a small molecule inhibitor of PKA targeted to its catalytic subunit (KT5720), a peptide inhibitor targeted to its regulatory subunits (PKI), an inhibitor of a novel PKC (an nPKCη pseudosubstrate fragment), and an antioxidant (melatonin). Given these and other data, we propose a model for redundant parallel pathways of Ca(2+)-dependent plasmalemmal sealing of injured neurons mediated in part by nPKCs, cytosolic oxidation, and cAMP activation of PKA and Epac. We also propose that the evolutionary origin of these pathways and substances was to repair plasmalemmal damage in eukaryotic cells. Greater understanding of vesicle interactions, proteins, and pathways involved in plasmalemmal sealing should suggest novel neuroprotective treatments for traumatic nerve injuries and neurodegenerative disorders.
Model of plasmalemmal sealing. Ca…
Model of plasmalemmal sealing. Ca 2+ flowing inward through the damage site activates…
Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons
GABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.
Conflict of interest statement
The authors declare no competing interests.
Fig. 1. Distribution of hypothalamus Lhx6 -expressing…
Fig. 1. Distribution of hypothalamus Lhx6 -expressing neurons.
2% of all hypothalamic GABAergic neurons during development. I Schematic distribution of Lhx6-expressing neurons across the dorsolateral hypothalamus (red = neurons that continue to express Lhx6, purple = neurons that transiently expressed Lhx6) across ZIv (zona incerta ventral), ZIl (zona incerta lateral), LH (lateral hypothalamus), DMH (dorsomedial hypothalamus), VMH (ventromedial hypothalamus), and PH (posterior hypothalamus). J–C′ Lhx6-antibody staining (gray), tdTomato expression from Lhx6 Cre/+ Ai9 line (red), NeuN (yellow) in ZIv (J–M), ZIl (N, Q), DMH (R–U), LH (V–Y), PH (Z–C′). L = lateral, M = medial. White arrowheads show neurons that transiently expressed Lhx6, and white arrows show neurons continue to express Lhx6). D′ A bar graph showing the percentage of tdTomato + and Lhx6-expressing neurons over the total number of tdTomato + neurons. Scale bar = 0.45 mm (A), 0.5 mm (B, F, G), 0.55 mm (E), 0.1 mm (I–C′). All bar graphs (D′) show mean and standard error of the mean (SEM), with individual data points plotted.
Fig. 2. Lhx6 in the hypothalamus is…
Fig. 2. Lhx6 in the hypothalamus is necessary for neuronal survival.
Fig. 3. Diverse subtypes of mature hypothalamic…
Fig. 3. Diverse subtypes of mature hypothalamic Lhx6-expressing neurons.
Fig. 4. scRNA-Seq identifies molecular markers of…
Fig. 4. scRNA-Seq identifies molecular markers of spatially distinct domains of hypothalamic Lhx6 neurons.
Fig. 5. Dlx1/2, Nkx2-2 , and Nkx2-1…
Fig. 5. Dlx1/2, Nkx2-2 , and Nkx2-1 are expressed in distinct spatial domains of hypothalamic…
Fig. 6. Dlx1/2, Nkx2-2 , and Nkx2-1…
Fig. 6. Dlx1/2, Nkx2-2 , and Nkx2-1 mediate patterning of discrete spatial domains of hypothalamic…
Fig. 7. Nkx2.2-expressing Lhx6 ZI neurons respond…
Fig. 7. Nkx2.2-expressing Lhx6 ZI neurons respond to increased sleep pressure.
We would like to thank B. Miller, B. Seeley, C. Lomen-Hoerth and the members of the Finkbeiner lab for their generous support and advice. H. Zahed and J. Margulis deserve special acknowledgment for their assistance. We thank G. Howard for editorial assistance and K. Nelson for administrative assistance. We also thank G. Yu and J. Herz (University of Texas, Southwestern) for anti-TDP43 antibodies. This work was supported by National Institutes of Neurological Disorders and Stroke grants K08 NS072233 (to S.J.B.), 3R01 NS039074, R01 NS083390, R43 NS081844 and U24 NS078370 (to S.F.) the ALS Association (S.F.) the Robert Packard Center for ALS Research and the William H. Adams Foundation (S.F.) and Target ALS (S.F.). Additional support was provided by the Roddenberry Stem Cell Program (to S.F.), the Taube-Koret Center for Neurodegenerative Disease (S.F.), the Hellman Family Foundation Alzheimer's Disease Research Program (S.F.), the Protein Folding Diseases Initiative at the University of Michigan (S.J.B.) and the California Institute of Regenerative Medicine TR4-06693 (S.F.) and U01 MH1050135 (S.F.). The animal care facility was partly supported by an US National Institutes of Health Extramural Research Facilities Improvement Program Project (C06 RR018928).
Mitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival
Mitochondrial dysfunction is central to the pathogenesis of neurological disorders. Neurons rely on oxidative phosphorylation to meet their energy requirements and thus alterations in mitochondrial function are linked to energy failure and neuronal cell death. Furthermore, in neurons, dysfunctional mitochondria are reported to increase the steady-state levels of reactive oxygen species derived from the leakage of electrons from the electron transport chain. Research aimed at understanding mitochondrial dysfunction and its role in neurological disorders has been primarily geared towards neurons. In contrast, the effects of mitochondrial dysfunction in glial cells' function and its implication for neuronal homeostasis and brain function has been largely understudied. Unlike neurons and oligodendrocytes, astrocytes and microglia do not degenerate upon the impairment of mitochondrial function, as they rely primarily on glycolysis to produce energy and have a higher antioxidant capacity than neurons. However, recent evidence highlights the role of mitochondrial metabolism and signaling in glial cell function. In this work, we review the functional role of mitochondria in glial cells and the evidence regarding its potential role regulating neuronal homeostasis and disease progression.
Keywords: Astrocytes Calcium Free fatty acid oxidation Glycolysis Inflammation Microglia Mitochondria Oligodendrocytes Redox.
Copyright © 2017 Elsevier B.V. All rights reserved.
Neuronal metabolism, redox homeostasis and…
Neuronal metabolism, redox homeostasis and signaling are supported by neighboring glial cells. 1.1:…
Mitochondrial metabolism and signaling in…
Mitochondrial metabolism and signaling in astrocytes. 2.1: Glucose in astrocytes is used for…
IRF4 is a novel mediator for neuronal survival in ischaemic stroke
Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4-SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4-SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.
The expression of IRF4 is…
The expression of IRF4 is elevated during middle cerebral artery occlusion and oxygen…
The expression of IRF4 is…
The expression of IRF4 is elevated during middle cerebral artery occlusion and oxygen…
Depletion of IRF4 in neurons…
Depletion of IRF4 in neurons led to potentiated cerebral injury. ( a –…
Neuron-specific IRF4 overexpression is cerebroprotective…
Neuron-specific IRF4 overexpression is cerebroprotective during stroke. ( a and b ) The…
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The SMN protein contains GEMIN2-binding, Tudor and YG-Box domains.  It localizes to both the cytoplasm and the nucleus. Within the nucleus, the protein localizes to subnuclear bodies called gems which are found near coiled bodies containing high concentrations of small ribonucleoproteins (snRNPs). This protein forms heteromeric complexes with proteins such as GEMIN2 and GEMIN4, and also interacts with several proteins known to be involved in the biogenesis of snRNPs, such as hnRNP U protein and the small nucleolar RNA binding protein. 
SMN complex refers to the entire multi-protein complex involved in the assembly of snRNPs, the essential components of spliceosomal machinery.  The complex, apart from the "proper" survival of motor neuron protein, includes at least six other proteins (gem-associated protein 2, 3, 4, 5, 6 and 7. 
SMN has been shown to interact with:
SMN is evolutionarily conserved including the Fungi kingdom, though only fungal organisms with a great number of introns have the Smn gene (or the splicing factor spf30 paralogue). Surprisingly, these are filamentous fungus which have mycelia, so suggesting analogy to the neuronal axons. 
Killer competition: Neurons duke it out for survival
The developing nervous system makes far more nerve cells than are needed to ensure target organs and tissues are properly connected to the nervous system. As nerves connect to target organs, they somehow compete with each other resulting in some living and some dying. Now, using a combination of computer modeling and molecular biology, neuroscientists at Johns Hopkins have discovered how the target tissue helps newly connected peripheral nerve cells strengthen their connections and kill neighboring nerves. The study was published in the April 18th issue of Science.
“It was hard to imagine how this competition happens because the signal that leads cells to their targets also is responsible for keeping them alive, which begs the question: How do half of them die?” says David Ginty, Ph.D., a professor of neuroscience and investigator of the Howard Hughes Medical Institute.
Target tissues innervated by so-called peripheral neurons coax nerves to grow toward them by releasing nerve growth factor protein, or NGF. Once the nerve reaches its target, NGF changes from a growth cue to a survival factor. In fact, when some populations of nerve cells are deprived of NGF they die. To further investigate how this NGF-dependent survival effect works the researchers looked for genes that are turned on by NGF in developing nerve cells.
They found hundreds of genes that respond to NGF genes, some of which are involved in enhancing NGF’s effect. With the observation that NGF seems to control genes that improve NGF effectiveness, Ginty’s team hypothesized that this could be the way in which nerve cells compete with one another for survival. To test this idea the team turned to colleagues at the Mind/Brain Institute at Hopkins who specialize in computer modeling of such problems.
The computer model they built assigns each nerve cell its own mathematical equation that take into account how much NGF the cell encounters or how effective NGF can be to simulate a cell’s drive to survive. When they plugged in the model, it showed that over time-about 100 days or so-about half of the cells manage to survive, while the other half die.
But, in the developing mouse embryo, nerve cells that die do so over the course of two to three days just before birth. “So then we considered whether these nerves compete like other systems in the body, where those with stronger connections punish the weaker ones,” says Ginty. The team turned their attention to other genes they found to be NGF dependent two of which code for proteins that kill neighboring nerve cells and another is the receptor for these death proteins.
According to Ginty, nerves that connect to muscles undergo a similar process called synapse elimination where stronger connections stay connected and weaker ones are eliminated. The team wondered if this is also true of peripheral nerve cells competing for NGF availability and ultimate cell survival. To test this idea they plugged these three additional genes into their computer model, assuming that the stronger connected nerve cell punishes its neighbors by releasing the two proteins capable of killing. The computer model showed again, that half the nerve cells die over time, but this time the death occurred over two to three days rather than 100 days, just as in living animals.
To confirm that the model is accurate, the team went back to genetically altered mice. They predicted that removal of the punishment signals should delay cell death as observed in their early computer simulations. Indeed, nerve cells in mice lacking the receptor protein for the death signals died much slower than in mice with the receptor protein intact.
“I never would have believed that these three genes could speed up competition so much,” says Ginty. “But there it was in front of us-it was amazing.”