Neurotrophic factors (NTFs) are a family of

biomolecule A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or developmental biology, development. Biom ...

s – nearly all of which are

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s or small

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

s, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

and

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...

, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap. Currently, neurotrophic factors are being intensely studied for use in bioartificial nerve conduits because they are necessary ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...

'' for directing axon growth and regeneration. In studies, neurotrophic factors are normally used in conjunction with other techniques such as biological and physical cues created by the addition of cells and specific topographies. The neurotrophic factors may or may not be immobilized to the scaffold structure, though immobilization is preferred because it allows for the creation of permanent, controllable gradients. In some cases, such as neural drug delivery systems, they are loosely immobilized such that they can be selectively released at specified times and in specified amounts.

List of neurotrophic factors

Although more information is being discovered about neurotrophic factors, their classification is based on different cellular mechanisms and they are grouped into three main families: the neurotrophins, the CNTF family, and GDNF family.

Neurotrophins

Brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is structurally similar to NGF, NT-3, and

NT-4 Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the ''NTF4'' gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase Receptor tyrosine kinas ...

/5, and shares the TrkB receptor with NT-4. The brain-derived neurotrophic factor/TrkB system promotes thymocyte survival, as studied in the

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or '' T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders ...

of mice. Other experiments suggest BDNF is more important and necessary for neuronal survival than other factors. However, this compensatory mechanism is still not known. Specifically, BDNF promotes survival of

dorsal root ganglion A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...

neurons. Even when bound to a truncated TrkB, BDNF still shows growth and developmental roles. Without BDNF (homozygous (-/-)), mice do not survive past three weeks. Including development, BDNF has important regulatory roles in the development of the

visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus ...

, enhancing neurogenesis, and improving learning and memory. Specifically, BDNF acts within the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...

. Studies have shown that

corticosterone Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rar ...

treatment and adrenalectomy reduces or upregulated hippocampal BDNF expression. Consistent between human and animal studies, BDNF levels are decreased in those with untreated major depression. However, the correlation between BDNF levels and depression is controversial.

Nerve growth factor

Nerve growth factor Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was ...

(NGF) uses the high-affinity receptor TrkA to promote

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can ...

ation and the differentiation of neurons. Studies have shown dysregulation of NGF causes hyperalgesia and pain. NGF production is highly correlated to the extent of

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

. Even though it is clear that exogenous administration of NGF helps decrease tissue inflammation, the molecular mechanisms are still unknown. Moreover, blood NGF levels are increased in times of stress, during

immune disease Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a ''primary'' immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature ...

, and with

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...

, amongst other conditions.

Neurotrophin-3

Whereas neurotrophic factors within the neurotrophin family commonly have a protein

tyrosine kinase receptor Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...

(Trk), Neurotrophin-3 (NT-3) has the unique receptor, TrkC. In fact, the discovery of the different receptors helped differentiate scientists' understanding and classification of NT-3. NT-3 does share similar properties with other members of this class, and is known to be important in neuronal survival. The NT-3 protein is found within the

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

intestinal epithelium The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functi ...

but its role in the function of each organ is still unknown.

Neurotrophin-4

CNTF family

The CNTF family of neurotrophic factors includes ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6),

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pi ...

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

leptin Leptin (from Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn dimi ...

, interferons (i.e., interferon-α, ), and oncostatin M.

Ciliary neurotrophic factor

Ciliary neurotrophic factor affects embryonic

motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirect ...

sensory neurons, and ciliary neuron hippocampal neurons. It is structurally related to leukemia inhibitory factor (LIF), interleukin 6 (IL-6), and oncostatin M (OSM). CNTF prevents degeneration of motor neurons in rats and mice which increases survival time and motor function of the mice. These results suggest exogenous CNTF could be used as a therapeutic treatment for human degenerative

motor neuron disease Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

s. It also has unexpected

-like characteristics as it causes weight loss.

GDNF family

The GDNF family of ligands includes glial cell line-derived neurotrophic factor (GDNF), artemin,

neurturin Neurturin (NRTN) is a protein that is encoded in humans by the ''NRTN'' gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neur ...

, and

persephin Persephin is a neurotrophic factor in the glial cell line-derived neurotrophic factor (GDNF) family. Persephin shares around a 40% similarity in amino acid sequence compared to GDNF and neurturin, two members of the GDNF family. Function Perse ...

Glial cell line-derived neurotrophic factor

Glial cell line-derived neurotrophic factor (GDNF) was originally detected as survival promoter derived from a glioma cell. Later studies determined GDNF uses a receptor tyrosine kinase and a high-affinity ligand-binding co-receptor

GFRα The GDNF family receptor-α (GFRα) proteins are a group of co-receptor A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological ...

. GDNF has an especially strong affinity for dopaminergic (DA) neurons. Specifically, studies have shown GDNF plays a protective role against MPTP toxins for DA neurons. It has also been detected in motor neurons of embryonic rats and is suggested to aid development and to reduce

axotomy An axotomy is the cutting or otherwise severing of an axon. Derived from axo- (=axon) and -tomy (=surgery). This type of denervation is often used in experimental studies on neuronal physiology and neuronal death or survival as a method to better ...

Artemin

Neurturin

Persephin

Ephrins

The ephrins are a family of neurotrophic factors that signal through

eph receptor Eph receptors (Ephs, after erythropoietin-producing human hepatocellular receptors) are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of re ...

s, a class of receptor tyrosine kinases; the family of ephrins include ephrin A1, A2, A3, A4, A5, B1, B2, and B3.

EGF and TGF families

The EGF and TGF families of neurotrophic factors are composed of

epidermal growth factor Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds. EGF was originally de ...

, the neuregulins, transforming growth factor alpha (TGFα), and

transforming growth factor beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

(TGFβ). They signal through receptor tyrosine kinases and serine/threonine protein kinases.

Other neurotrophic factors

Several other biomolecules that have identified as neurotrophic factors include: glia maturation factor,

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...

insulin-like growth factor 1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans ...

(IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF),

platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...

(PDGF), pituitary adenylate cyclase-activating peptide (PACAP), interleukin-1 (IL-1), interleukin-2 (IL-2),

interleukin-3 Interleukin 3 (IL-3) is a protein that in humans is encoded by the ''IL3'' gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the prote ...

(IL-3), interleukin-5 (IL-5), interleukin-8 (IL-8),

macrophage colony-stimulating factor The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types. Eukaryotic cells als ...

(M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and neurotactin.

References

{{Growth factor receptor modulators Neurochemistry