How do growth factors cause cell differentiation?
As well as causing the proliferation of cells, growth factors can promote differentiation and even the death of cells. For example, differentiation of neuronal progenitor cells to funcitonal neuronal cell is regulated by so-called neurotrophic growth factors. As with the proliferative growth factors, neurotrophic growth factors initiate a complex cascade of events by binding to receptor proteins that span the cell surface:
- Neurotrophic Growth Factor Binding
Neurotrophic growth factors are proteins that bind to specific receptors on the surface of partly differentiated neural progenitor cells. These receptors are typically tyrosine kinase receptors, which, upon binding to their respective growth factors, undergo a conformational change that activates their kinase activity.
- Receptor Activation
The binding of growth factors to their receptors leads to the dimerization (pairing) and autophosphorylation (addition of phosphate groups) of the receptors. This phosphorylation activates the receptor’s intrinsic kinase activity, which then phosphorylates downstream signalling molecules.
- Signal Transduction Pathways
Activated receptors initiate a cascade of intracellular signalling pathways. Key pathways involved in neural differentiation and maturation include:
- MAPK/ERK Pathway (sown in the figure above): This pathway is crucial for cell proliferation and differentiation. Activation of the MAPK/ERK pathway which ends with the phosphorylation of ERK.
- PI3K/Akt Pathway: This pathway promotes cell survival and growth. It also plays a role in neuronal differentiation by regulating the activity of a range of transcription factors and other proteins that drive the maturation process.
- JAK/STAT Pathway: This pathway is involved in the response to cytokines and growth factors. It can influence the expression of genes that promote neural differentiation and inhibit apoptosis (programmed cell death).
- Notch Signalling Pathway: This pathway is critical for maintaining the balance between neural progenitor cell proliferation and differentiation. Activation of Notch signalling can either promote or inhibit differentiation depending on the cellular context.
- Gene Expression Regulation
The activation of these signalling pathways leads to the activation or repression of specific transcription factors. These transcription factors then enter the nucleus and bind to the DNA, regulating the expression of genes that are essential for neural differentiation and maturation. Key transcription factors involved in neural differentiation include:
- Neurogenin (Ngn): Promotes the differentiation of neural progenitors into neurons.
- NeuroD: Involved in the maturation and survival of newly formed neurons.
- Sox2: Maintains the pluripotency of neural stem cells and regulates the balance between self-renewal and differentiation.
- Mash1 (Ascl1): Plays a crucial role in the early stages of neurogenesis by promoting the differentiation of neural progenitor cells into neurons.
- Cell Cycle Exit
As cells differentiate, they tend to lose their capacity to proliferate. As neural progenitor cells receive signals from growth factors, they undergo changes in gene expression that lead to cell cycle exit. This is a critical step where cells stop proliferating and start differentiating into specific neural cell types, such as neurons, astrocytes, or oligodendrocytes. The regulation of cell cycle exit is tightly controlled by various cell cycle inhibitors, such as CDK/Cyclin, and transcription factors.
- Differentiation
For neuronal cells, differentiation and maturation triggered by neurotrophic factors proceed along a series of steps:
- Cytoskeletal Reorganization
Differentiation involves significant changes in the cytoskeleton of the cell. Growth factors induce the reorganization of the cytoskeleton, which is essential for the morphological changes that occur during differentiation. For example, the extension of neurites (axons and dendrites) in neurons is a key aspect of their maturation and is regulated by growth factors. A stable supply of neurotrophic growth factors (e.g BDNF, GDNF) promotes axonal extension and arborization (branching).
- Synaptogenesis and Maturation
In the final stages of differentiation, neurons form synapses, which are the connections between neurons that allow for communication. Growth factors such as BDNF and NT-3 play crucial roles in synaptogenesis. These factors promote the formation of synaptic connections, and the strengthening of synapses through synaptic plasticity mechanisms.
- Functional Integration
As neurons mature, they integrate into existing neural circuits. This involves the establishment of functional synaptic connections and the ability to generate and propagate electrical signals. Growth factors continue to support the survival and function of mature neurons, ensuring they remain integrated within the neural network.
- Astrocyte and Oligodendrocyte Differentiation
Apart from neuronal differentiation, neural progenitor cells can differentiate into glial cells, such as astrocytes and oligodendrocytes. Different growth factors influence this process:
- Ciliary Neurotrophic Factor (CNTF): Promotes the differentiation of neural progenitors into astrocytes.
- Platelet-Derived Growth Factor (PDGF): Promotes the differentiation of neural progenitors into oligodendrocytes, which are responsible for the formation of myelin sheaths around axons, facilitating rapid signal transmission.
- Maintenance and Survival
Even after differentiation and maturation, growth factors continue to play a vital role in maintaining the health and function of neural cells. They support cell survival, protect against apoptosis, and help in the repair and regeneration of neural tissues following injury. For example:
- Nerve Growth Factor (NGF): Essential for the survival and maintenance of sympathetic and sensory neurons.
- Glial Cell Line-Derived Neurotrophic Factor (GDNF): Supports the survival of various types of neurons, including motor neurons and dopaminergic neurons.
IMAGE How growth factors cause cell differentiation CREDIT: Cell Guidance Systems Ltd
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