schwann cell

Neurons - Anatomy Overview

Going to be covering nerves and synapses this week so here’s a recap!

  • Soma (cell body) contains the nucleus which produces RNA to support cell functions, + organelles surrounding the nucleus which are mostly made of up endoplasmic reticulum. Supports and maintains the functioning of the neuron.
  • Dendrites - cellular extensions with many branches ‘dendritic tree’. majority of input occurs via the dendritic spine. The sum of all excitatory (neuron fires) or inhibitory (prevents firing) signals determines whether the neuron fires or not. If firing the action potential is transmitted down the axon.
  • Axon - fine, cable-like projection that can extend thousands of times the diameter of the soma in length. The axon carries nerve signals away from the soma (and also carries some types of information back to it). Can undergo branching - communication with target cells. 
  • Axon hillock - where the axon emerges from the soma. the part of the neuron that has the greatest density of voltage-dependent sodium channels - therefore the most easily excited part of the neuron and the spike initiation zone for the axon - most negative action potential threshold. Can also receive input from other neurons.
  • Axon terminal where neurotransmitters are released into the synaptic cleft to signal the next neuron

Myelin sheath

Myelin is a fatty material that wraps around axons and increases the speed of electrical transmission between neurons. It is broken up by nodes of Ranvier, between which electrical impulses jump. Myelin is produced by schwann cells in the PNS and oligodendrocytes in the CNS.

Classes of neurons

Sensory neurons bring information into the CNS so it can be processed.

Motor neurons get information from other neurons and convey commands to  muscles, organs and glands.

Interneurons,found only in the CNS, connect one neuron to another. 

Types of neuron

Multipolar neurons have one axon and many dendritic branches. These carry signals from the central nervous system to other parts of the body eg muscles and glands.

Unipolar neurons are also known as sensory neurons. They have one axon and one dendrite with branches. Pass signals from the outside of the body, such as touch, along to the central nervous system.

Bipolar neurons have one axon and one dendrite branch. They pass signals from one neuron to the next inside the central nervous system.

Pyramidal neurons have one axon and two main dendrite branches. These cells pass signals inside the brain and tell the muscles to move.

Purkinje neurons are found in the cerebellum, controlling balance, coordination, and timing of actions. They have one axon and a dense and complicated dendrite arrangement.

Oncogenes and tumour suppressors are mutation targets promoting the onset and maintenance of cancer. Oncogenic mutations result in gain-of-function and deregulation of the function of the oncoprotein that they encode. Tumour suppressors act to run quality checking of DNA, keep cell cycle checkpoints, and shut down mitogenic signals; mutations in genes encoding tumour suppressors can lead to absence of these checks and give activated oncoproteins the chance to run riot in a cell. Co-incidence of mutations in oncogenes and tumour suppressor genes potentially leads to cancer.

Oncogenes

Ras is a small G protein involved in a whole host of cellular functions. Mutation of Ras at a functional site can lead to a pleiotropic phenotype. Oncogenic Ras causes inappropriate signalling through its three pathways: MAPK, PI3K, and RalGEF. Signalling through the PI3K activates antiapoptotic Akt (PKB), which acts to promote cell survival. Signalling through RalGEF causes cell motility by formation of filopodia (Cdc42) and lamellipodia (Rac), which may be associated with metastasis. Signalling through MAPK actually causes the expression of some Ras signalling inhibitors (Sproutys, SPREDs, GAPs) which shuts down the signal in normal cells.

Myc is a transcription factor with more than 8000 transcription targets. Deregulated Myc leads to cell proliferation, but does not block apoptosis. Thus, it leads to a modest amount of growth before it is eradicated by apoptosis. Inhibition of apoptosis by antiapoptotic Bcl-xL is tumourigenic in cells expressing Myc highly. Additionally, Myc is thought to contribute to the tumour microenvironment, immune evasion, and inhibition of differentiation.

Ras and Myc work together by combining their abilities. Myc promotes cell proliferation and disfavours differentiation, and Ras inhibits apoptosis. The combination of the two means that cells are allowed to proliferate without triggering apoptosis. Ras actually activates Myc in normal cells - but in normal cells, activation is transient. Ras stabilises Myc by phosphorylation on S62 through MEK signalling, but also promotes its degradation by phosphorylation on T58 through PI3K signalling. The result is transient activation of Myc by Ras. Mutations which ultimately block phosphorylation at T58 will switch activation by Ras from a transient to a constitutive response.

Tumour suppressors

p53 is the so-called guardian of the genome. High Myc and oncogenic Ras cause stabilisation and activation of p53. p53 gets two bites at the cherry to combat the inheritance of damaged genomes: at the point of DNA damage, p53 arrests the cell until the DNA is repaired. p53 decides whether the cell enters senescence or apoptosis - its own state of post-translational modifications and the genomic context of its target genes (p53 is also a TF) on the genome in that particular cell both play a role in which way the scale tips. In this way, p53’s second bite of the cherry is the selection of apoptosis in cells whose DNA is damaged beyond repair.

Rb is the keeper of the G1/S checkpoint. Loss of both copies of the Rb gene leads to retinoblastoma. Familial retinoblastoma predisposes heterozygotes with a heightened risk of retinoblastoma by loss of heterozygosity - loss of their only functional copy. This can occur by mutation, but also by mitotic recombination, gene conversion, and nondisjunction. Cells null for Rb can still enter G0 phase, as p107 and p130 share some redundant functions with Rb.

NF1 displays the phenomenon of haploinsufficiency. Nf1-/- Schwann cells can be complemented for the wild-type by Nf1+/+ mast cells, but not Nf1+/- mast cells. The former gives the wild-type; the latter causes neurofibromas.

VHL suppresses the hypoxic response in normoxia by mediating the ubiquitin-associated degradation of HIF-1α in normoxia. Loss of VHL leads to a hypoxic response no matter the oxygen level.

Further reading:

  • Hanahan, D.; Weinberg, R.A. 2011. “Hallmarks of cancer: The next generation.” Cell 144:646-674.
  • Lowe, S.W.; Cepero, E.; Evan, G. 2004. “Intrinsic tumour suppression.” Nature 432:307-315.
  • Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. 2011. “RAS oncogenes: Weaving a tumorigenic web.” Nature Reviews Cancer 11:761-774.
  • Soucek, L.; Evan, G.I. 2010. “The ups and downs of Myc biology.” Current Opinion in Genetics and Development 20:91-95.
  • Vousden, K.H.; Prives, C.; 2009. “Blinded by the light: The growing complexity of p53.” Cell 137:413-431.
  • Burkhart, D.L.; Sage, J. 2008. “Cellular mechanisms of tumour suppression by the retinoblastoma gene.” Nature Reviews Cancer 8:671-682.
Study Identifies Unexpected Clue to Peripheral Neuropathies

New research shows that disrupting the molecular function of a tumor suppressor causes improper formation of a protective insulating sheath on peripheral nerves – leading to neuropathy and muscle wasting in mice similar to that in human diabetes and neurodegeneration.

Scientists from Cincinnati Children’s Hospital Medical Center report their findings online Sept. 26 in Nature Communications. The study suggests that normal molecular function of the tumor suppressor gene Lkb1 is essential to an important metabolic transition in cells as peripheral nerves (called axons) are coated with the protective myelin sheath by Schwann glia cells.

“This study is just the tip of the iceberg and a fundamental discovery because of the unexpected finding that a well-known tumor suppressor gene has a novel and important role in myelinating glial cells,” said Biplab Dasgupta PhD, principal investigator and a researcher at the Cincinnati Children’s Cancer and Blood Diseases Institute (CBDI).  “Additional study is needed, as the function of Lkb1 may have broader implications – not only in normal development, but also in metabolic reprogramming in human pathologies. This includes functional regeneration of axons after injury and demyelinating neuropathies.”

The process of myelin sheath formation (called myelination) requires extraordinarily high levels of lipid (fat) synthesis because most of myelin is composed of lipids, according to Dasgupta. Lipids are made from citric acid which is produced in the powerhouse of cells called mitochondria. Success of this sheathing process depends on the cells shifting from a glycolytic to mitochondrial oxidative metabolism that generates citric acid, the authors report.

Dasgupta’s research team used Lkb1 mutant mice in the current study. Because the mice did not express Lkb1 in myelin forming glial cells, this allowed scientists to analyze its role in glial cell metabolism and formation of the myelin sheath coating.

When the function of Lkb1 was disrupted in laboratory mice, it blocked the metabolic shift from glycolytic to mitochondrial metabolism, resulting in a thinner myelin sheath (hypomyelination) of the nerves. This caused muscle atrophy, hind limb dysfunction, peripheral neuropathy and even premature death of these mice, according to the authors.

Peripheral neuropathy involves damage to the peripheral nervous system – which transmits information from the brain and spinal cord (the central nervous system) to other parts of the body, according to the National Institute of Neurological Disorders and Stroke (NINDS). There are more than 100 types of peripheral neuropathy, and damage to the peripheral nervous system interferes with crucial messages from the brain to the rest of the body.

The scientists also reported that reducing Lkb1 in Schwann cells decreased the activity of critical metabolic enzyme citrate synthase that makes citric acid. Enhancing Lkb1 increased this activity.

They tested the effect of boosting citric acid levels in the Lbk1 mutant Schwann cells. This enhanced lipid production and partially reversed myelin sheath formation defects in Lbk1 mutant Schwann cells. Dasgupta said this further underscores the importance of Lbk1 and the production of citrate synthase.

Dasgupta and his colleagues are currently testing whether increasing the fat content in the Lbk1 mutant mice diet improves hypomyelination defects. The researchers emphasized the importance of additional research into the laboratory findings to extend their relevance more directly to human disease.

Spinal nerve anatomy.

The image above displays a caricature version of the spinal nerves found within our spinal cord. The pink arrow points to the spinal nerve which is surrounded by a membrane referred to as the epineurium (light green). Within the nerves are bundles of neurons that make up what are referred to as fascicles. Fascicles also consist of a membrane known as the perineurium (blue). The fascicles contain neurons that are surrounded by endoneuronium (red). These neurons are also wrapped by Schwann cells (orange) that contain myelin, and hence, are referred to as myelinated axons (dark green).