Growth and Trophic factors

What are growth and trophic factors generally

What is a classical target-derived neurotrophic factor?

Soluble, diffusible polypeptides that regulate neural development, survival, function, plasticity, regeneration, and repair.

A factor released in limited amounts by a neuron’s projection target that regulates survival and differentiation during development and maintains specialised function in adulthood.

What four questions should always be asked about a growth factor?

Which factor is present? Where is it produced? When is it produced? Which receptors are expressed?

What ultimately determines a trophic factor’s biological outcome?

The factor’s identity, location and timing, the receptors and co-receptors expressed, and how the signal reaches the cell body.

What type of competition occurs during development

Targets supply trophic support in limited amounts and quality, so not every neuron can obtain enough support to survive and stabilise its connection.

Those forming the most appropriate ligand–receptor relationships and successful target connections are stabilised while weaker/inappropriate connections are pruned or have cell death.

Examples of growth/trophic factors

NFCTI

Neurotrophins (NTs): development, neuronal survival

Fibroblast growth factor (FGF): originally discovered in fibroblast, proliferation, differentiation

Cytokines (CNTF (ciliary neurotrophic factor), LIF (leukemia inhibitory factor)): survival, inflammation

Transforming growth factors (TGFb, GDNF): development, regeneration

Insulin-like growth factors (IGF1): growth, metabolism

Do early developing neurons initially require trophic factors to survive?

Not necessarily. They can initially respond to trophic factors without being dependent on them for survival.

How do target-derived factors guide growing axons and what happens when the neuron connects to the target?

Target cells receive target signals; target tissue then release factors that form local gradients; responsive axons extend toward the source along the diffusion gradient and synapses with the target tissue when reached.

The neuron may develop target dependency where the neuron may rely on the target’s trophic support, so the removal of the target/trophic factor results in neuronal death.

What is the developmental purpose of target dependency?

It matches the number and phenotype of surviving neurons to the needs and trophic capacity of the target tissue.

How can a growth factor’s role change as innervation develops?

It can first promote extension, then branching and synaptogenesis after target contact, and later maintenance or pruning.

DRG explant grown without vs with NGF

What does this say about NGF

Without: produces limited neurite growth

With: Neurite number, length, outgrowth and survival increases

NGF promotes growth and survival

What is the immature version of NGF called and what is the structure of both mature and immature versions

Pro-NGF. cleaves to form NGF

Pro NGF: a dimer made of two identical NGF molecule subunits

What happens when radiolabeled NGF is injected into a peripheral target?

Why must a target-derived NGF signal reach the soma?

Axon terminals take it up and transport it retrogradely to DRG cell bodies. (eg in whisker barrels the protein was transported retrogradely through the DRG into SC and brain)

It must alter survival-related gene expression in the neuronal cell body.

Name the 4 factors in the neurotrophins family and their receptors

Nerve Growth Factor NGF= primary interaction is with Trk (receptor tyrosine kinase) A and p75NTR

Brain Derived Neurotrophic Factor BDNF: primary interaction with Trk B and p75NTR

Neurotrophin 4/5 NT4/5= primary interaction with Trk B and p75NTR

Neurotrophin 3 NT3= primary interaction with Trk C and p75NTR

Small amount of redundancy in that NT3 can also potentially interact with Trk B & A and NT4/5 can potentially interact with Trk C.

What can P75NTR induce

What can occur when p75NTR binds to a neurotrophin by itself vs when Trk and p75NTR are co-expressed?

Differentiation, survival, maintenance and death

By itself, the death domain of P75 can bind to a neurotrophin which can bring about an apoptotic event however with Trk neurotrophin signalling can be enhanced, favouring survival or differentiation.

What can occur when a proneurotrophin binds p75NTR with sortilin?

What about when Nogo binds to p75NTR?

Activate apoptosis or axonal pruning

Nogo (myelin associate dprotein that inhibits axon outgrowth) interacting through p75NTR-associated receptor complexes, including LINGO-1 (leucine rich repeat and immunoglobin-like domain-containing protein 1 (Nogo coreceptor)), produces a repulsive/inhibitory signal for axon growth telling the fibre to grow away from the site

NGF nerve growth factor roles

GMSAP

DRG neurite growth and survival

Maintenance of mature neural functions

Synaptic plasticity (more successful in PNS as it allows for more regenerative events compared to CNS),

Memory/cognition

Alzheimer-related biology: can affect memory, cognition and loss of the neurons are the disease progresses

PNS repair: NGF highly expressed after injury of sciatic nerve, diff injury reponses in CNS and PNS as there are different family of GF

Neurotrophin-3

When in development it appears, what it does (3)

Appears early,

Acts as mitogen for neural crest cells that migrate from PNS,

Contributes to neuronal differentiation in CNS particularly motor and corticospinal neurons (critical for fine motor control)

Supports DRG neruons eg large proprioceptive

Brain derived neurotrophic factor BDNF

Supports what, roles (3)

Supports DRG neurons particularly parasympathetic neurons in periphery

Expressed in many places: Trophic for dopaminergic and GABAergic neurons & supports cells in visual system

Arborization (sprouting) factor or some neurons including RGC

Involved in synaptic plasticity esp neurogenesis through exercise, learning, response, memory

Conc in brain 20x of NGF

What is anterograde transport?

What is retrograde transport?

Movement from the cell body toward the axon terminal, associated with kinesin; it delivers proteins, organelles, receptors, and neuron-derived signals distally.

Movement from the axon terminal toward the soma, associated with dynein; it carries internalised signalling endosomes that change gene expression and survival.

What is paracrine signalling?

What is autocrine signalling?

What is a signalling endosome?

A nearby cell releases a factor that acts locally on neighbouring cells.

A cell releases a factor to which it also responds, allowing self-regulation of survival, growth, or phenotype.

An internalised ligand–receptor complex that preserves an active signal during transport, often from a distal axon to the soma.

Differential tagging

what it is, an example, and why is it needed

• GF binds to receptor, is internalized and processed into endosome which is tagged to show where the signal came from

  • tagging can occur within seconds to minutes, BDNF tagged quick

• The tagged endosome is transported to the cell body where a signal transduction event happens that control neuronal survival, growth etc.

example:

• NGF released from target and binds to Trk A at axon terminal. NGF-TrkA complex interalized and transported to the soma retrogradely, stimulating production of more TrkA. New TrkA receptors transported from soma to axon terminals by RAB11 where more NGF binds and signal back to the cell body. Forms a positive feedback loop.

• each source tagged with diff proteins so the cell known where it came from

How does exercise affect BDNF?

• Exercise increases BDNF mRNA and protein, it helps to retain tissue for longer hence stay healthy longer so more survival

• It enhances cognitive function as we overexpress BDNF the more exercise we do which reinforces learning

• Increased BDNF=Neuronal survival, hippocampal neurogenesis, exploration-related reinforcement, synaptic plasticity, learning, and memory.

BDNF

How is it synthesized (2)

Why do multiple BDNF transcripts and forms matter?

• precursor Pre-proBDNF is cleaved to 32 kDa proBDNF, which is then cleaved intracellularly by enzymes to make mature BDNF. Or it can be secreted extracellularly as proBDNF and cleaved by extracellular proteases to mature BDNF (mBDNF).

• They allow fine control over where, when, and how BDNF acts

Is proBDNF simply an inactive precursor?

Why can proBDNF and mature BDNF produce different effects?

How can proBDNF and mature BDNF be released?

No. ProBDNF is a signalling molecule in its own right.

They favour different receptor complexes and therefore different biological outcomes.

Both can be sorted into activity-regulated secretory vesicles.

Which factors promoted axonal growth in experimental spinal-cord injury and what benefits can the GF provide? (4)

How can they be delivered

NT-3, BDNF, GDNF (glial cell line derived NF), NGF, and bFGF (basic fibroblast). Enhanced growth and function, rescue of axotomized neurons, reduced atrophy, and prolonged expression of regeneration-associated genes.

Virally or direct administration

How can scaffolds be used in growth-factor therapy?

Which engineered cell types can deliver growth factors?

Natural or synthetic scaffolds can localise and control factor presentation while providing a path for growing axons.

OEGs, Schwann cells, or neural progenitor cells engineered to release factors.

What variables must effective growth-factor therapy control?

What is the main therapeutic principle for trophic-factor repair?

Factor identity, dose, receptor-bearing target population, location, timing, and duration.

Effective therapy requires precise spatial and temporal signalling, not simply adding more growth factor.

How might growth-factor gradients be arranged to promote reconnection?

Why will one factor combination not repair every axonal population?

Reduce signals at the lesion after initial support and present them farther downstream to draw axons toward appropriate targets.

Different axonal populations express different receptors and respond to different factor combinations.