MSc III Sem PPT: Axonal Guidance and Neurotropic Factors

SGT UNIVERSITY Gurugram Subject – Advanced Neurobiochemistry And Immunology Topic – Axonal Guidance and Neurotropic Factors Submitted to Presented by Dr.S...

SGT UNIVERSITY Gurugram Subject – Advanced Neurobiochemistry And Immunology Topic – Axonal Guidance and Neurotropic Factors Submitted to Presented by Dr.Shweta Tripathi Ritu and Reetika Assistant Professor MNNT III Sem FAHS, FAHS, SGT University SGT University Axonal Guidance and Neurotropic Factors Axonal guidance is the intricate process by which growing axons navigate the developing nervous system to reach their correct target cells. This journey is guided by a complex interplay of molecular cues and cellular interactions. Neuronal growth factors play a crucial role in supporting axon growth and survival during this journey. Role of Neuronal Growth Factors Neuronal growth factors are proteins that promote the survival, growth, and differentiation of neurons. These essential molecules act as guiding signals, influencing axon elongation, branching, and target selection. 1 Promoting Survival 2 Stimulating Growth Growth factors act as life- They trigger the sustaining signals, production of proteins and preventing neurons from other molecules necessary undergoing apoptosis for axon elongation and (programmed cell death). branching. 3 Guiding Pathfinding Growth factors influence the direction of axon growth, ensuring they reach their appropriate targets. Molecular Mechanisms of Axon Guidance Axon guidance is a complex process involving intricate molecular interactions. Guidance cues, such as chemoattractants and chemorepellents, bind to specific receptors on the axonal surface, triggering intracellular signaling cascades that influence axon behavior. 1 Signal Reception Guidance cues bind to receptors on the axonal surface, initiating a signaling cascade. 2 Signal Transduction The signal is relayed through a series of intracellular molecules, activating downstream effector proteins. 3 Growth Cone Response The signal alters the cytoskeleton and growth cone dynamics, directing axon growth towards or away from the cue. Axon Development and Growth Cone Formation 1 Axon Initiation Axon development begins with the formation of a growth cone, a specialized structure at the tip of the axon. 2 Growth Cone Morphology The growth cone is characterized by filopodia and lamellipodia, which serve as exploratory structures that sense the environment. 3 Axon Extension The growth cone is highly dynamic and constantly extends, retracts, and turns as it navigates the environment towards its target.  Growth Cone Structure and Function Growth cones, the dynamic tips of axons, are responsible for sensing and responding to guidance cues. They have a complex structure, consisting of filopodia and lamellipodia, which explore the environment and direct axon growth. Filopodia Lamellipodia Cytoskeleton Slender, finger-like projections A flattened, sheet-like structure A network of microtubules and that extend from the growth that forms a wider area of actin filaments that provides cone, probing the environment contact with the extracellular structural support and for guidance cues. matrix. facilitates growth cone movement. The Role of the Cytoskeleton in Growth Cone Dynamics The cytoskeleton of the growth cone, composed of microtubules and actin filaments, plays a crucial role in shaping the growth cone, driving its motility, and mediating its responses to guidance cues. Microtubules Growth Cone Extension Microtubules extend from the axon shaft into the central region, providing structural support and serving as tracks for Microtubule polymerization and actin filament assembly drive intracellular transport. the extension of the growth cone, propelling it forward. 1 2 3 4 Actin Filaments Growth Cone Retraction Actin filaments are highly dynamic and form a network in the Microtubule depolymerization and actin filament disassembly lamellipodia and filopodia, driving their extension and retraction. contribute to the retraction of the growth cone, allowing it to change direction. Molecular Signals in Axonal Guidance Attractive Signals Repulsive Signals These signals draw the growth These signals push the growth cone towards its target, often cone away from specific areas, guiding it along specific preventing it from straying into pathways. They act as 'pulling inappropriate regions. They act forces' that guide the axon in as 'pushing forces' to steer the the right direction. axon away from undesirable areas. Netrin A protein family that acts as both attractive and repulsive signals. It guides axons in the developing nervous system towards specific target cells, influencing their final destination. Flowchart of Axonal Guidance 1 Growth Cone Formation The axon develops a growth cone at its tip, which is a dynamic structure responsible for sensing and responding to guidance cues. 2 Signal Reception The growth cone receives signals from its environment, including attractants and repellents, through receptors on its surface. 3 Cytoskeletal Rearrangement The signals trigger a cascade of events leading to the rearrangement of the cytoskeleton within the growth cone, directing its movement. 4 Axon Extension The growth cone extends the axon in the direction of attractive signals, guided by the dynamic cytoskeletal changes. 5 Target Recognition When the axon reaches its target cell, the growth cone recognizes specific signals indicating its final destination. Axon Pathfinding and Target Selection Axon pathfinding involves a series of decisions as axons navigate the intricate pathways of the nervous system. This journey is guided by a combination of guidance cues, growth factors, and interactions with other cells. Initial Growth Axons extend from the cell body, exploring the surrounding environment. Guidance Cue Interactions Axons respond to guidance cues, directing their growth towards or away from specific targets. Target Recognition Axons recognize their specific targets and establish connections, forming synapses. Attractive and Repulsive Guidance Cues Attractive cues attract axons towards their target cells, while repulsive cues guide axons away from inappropriate pathways. These cues act in a coordinated manner to ensure precise axonal navigation. Attractive Cues These cues act like magnets, drawing axons towards their targets, promoting proper connections. Repulsive Cues These cues act like barriers, pushing axons away from inappropriate pathways, preventing misconnections. Chemoattractant and Chemorepellent Signals Chemoattractants Chemorepellents Gradient Formation These molecules attract axons, These molecules repel axons, Chemoattractants and promoting their growth towards preventing them from growing in chemorepellents are often specific target cells. Examples incorrect directions. Examples expressed in gradients, allowing include netrins, Slit2, and BDNF. include semaphorins, ephrins, and axons to sense direction and Slit1. navigate towards or away from specific targets. Guidance Cue Gradients Concentration Gradients Directional Growth Axon growth cones respond to differences in Guidance cue gradients establish a directional signal that concentration of guidance cues, moving towards higher guides the growth cone, ensuring that axons grow in the concentrations of attractants and away from higher correct direction towards their targets. concentrations of repellents. Guidance Cues and their Receptors in Axonal Pathfinding Axonal guidance is achieved through a complex interplay between guidance cues, secreted or membrane-bound molecules that influence growth cone behavior, and their receptors, which detect and transduce signals. Guidance Cue Receptor Function Netrin-1 DCC (Deleted in Attracts axons Colorectal Cancer) towards target cells Slit Robo (Roundabout) Repels axons from inappropriate pathways Semaphorin 3A Plexin-A1 Repels axons from inappropriate pathways Ephrins and Eph Receptors in Axon Guidance Eph Receptors These are transmembrane receptor tyrosine kinases found on the surface of neurons. Ephrins These are membrane-bound ligands that bind to Eph receptors, triggering signaling pathways. Repulsive Guidance Ephrin-Eph receptor interactions typically lead to repulsive guidance of axons, preventing them from crossing certain boundaries. Fine-Tuning Ephrin-Eph interactions can also contribute to the fine-tuning of axonal projections within specific target areas. Semaphorins and Neuropilins in Axon Guidance Semaphorins Neuropilins Function A family of Transmembrane Mediate repulsive secreted and receptors that guidance of membrane-bound bind to axons, ensuring proteins. semaphorins. correct pathfinding. Netrins and Deleted in Colorectal Cancer (DCC) Receptors Netrins DCC Receptors Axonal Growth Synapse Formation A family of secreted proteins Transmembrane receptors that Netrin-DCC interactions that act as chemoattractants bind to netrins, triggering promote axonal growth and Netrins also play a role in for axons. signaling pathways that guidance towards specific synapse formation, promote axonal growth. targets. contributing to the establishment of functional neural circuits. Slits and Robo Receptors in Axon Guidance Slits Robo Receptors A family of secreted proteins Transmembrane receptors that act as chemorepellents that bind to Slits, triggering for axons. signaling pathways that lead to axonal repulsion. Boundary Formation Slit-Robo interactions help to establish boundaries in the nervous system, guiding axons along specific pathways and preventing them from crossing into inappropriate areas. Neurotropic Factors Definition and Importance 1 What Are They? 2 Why Are They Important? Neurotrophic factors are a group of proteins They play a critical role that promote the in the development, survival, growth, and maintenance, and differentiation of repair of the nervous neurons. system. 3 Their Impact Neurotrophic factors influence neuronal function, plasticity, and response to injury. Neurotrophic Factors and their Receptors 1 Brain-Derived 2 Nerve Growth Factor Neurotrophic Factor (NGF) (BDNF) A key neurotrophic factor for A powerful neurotrophic factor sensory and sympathetic that supports the survival and neurons, promoting their growth of neurons, particularly survival, growth, and in the hippocampus and cortex. differentiation. 3 Neurotrophin-3 (NT-3) 4 Neurotrophin-4/5 (NT- 4/5) A neurotrophic factor that A neurotrophic factor that is promotes the survival and structurally similar to BDNF and differentiation of motor neurons plays a role in the development and other neuronal populations. and function of various neuronal populations. Role of Neurotrophic Factors in Axon Guidance 1 Survival Neurotrophic factors promote the survival of neurons, ensuring that only those with successful axonal connections are maintained. 2 Growth and Differentiation Neurotrophic factors stimulate the growth and differentiation of axons, enabling them to reach their correct targets. 3 Synapse Formation Neurotrophic factors contribute to the formation of synapses, strengthening the connections between neurons and establishing functional neural circuits. 4 Plasticity Neurotrophic factors play a role in neural plasticity, allowing for the adaptation and refinement of neuronal connections throughout life. Mechanism of Neurotrophic Factor Signaling Receptor Binding Neurotrophic factors bind to specific receptors on the surface of target neurons. Signal Transduction This binding activates a signaling cascade within the neuron, leading to changes in gene expression. Transcriptional Activation These changes in gene expression promote the production of proteins that support survival, growth, and guidance of axons. Nerve Growth Factor (NGF) Discovery Function Clinical Significance NGF was the first neurotrophic NGF plays a crucial role in the NGF has shown promise in factor to be discovered. development and maintenance treating various neurological of sensory and sympathetic disorders, including Alzheimer's It was isolated in the 1950s by neurons. disease and Parkinson's disease. Rita Levi-Montalcini and Stanley It promotes the survival, growth, Cohen. and differentiation of these neurons. Brain-Derived Neurotrophic Factor (BDNF) Synaptic Plasticity BDNF enhances synaptic plasticity, the ability of synapses to strengthen or weaken over time. Learning and Memory BDNF plays a critical role in learning and memory formation. Neuroprotection BDNF protects neurons from damage and promotes their survival. Ciliary Neurotrophic Factor (CNTF) Function Promotes survival and differentiation of motor neurons, retinal ganglion cells, and other neuronal populations. Clinical Applications Being explored for treatment of amyotrophic lateral sclerosis (ALS), retinal degeneration, and other neurological disorders. Potential Benefits Could improve motor function, protect neurons from degeneration, and promote nerve regeneration. Glial Cell Line-Derived Neurotrophic Factor (GDNF) 1 Discovery GDNF was first discovered in 1993. 2 Function GDNF plays a critical role in the survival and differentiation of dopaminergic neurons, which are essential for movement control. 3 Clinical Applications GDNF is being investigated for the treatment of Parkinson's disease and other neurodegenerative disorders. Implications in Nervous System Development Axonal guidance and neuronal growth factors are crucial for proper nervous system development. Disruptions in these processes can lead to neurological disorders, including autism, epilepsy, and Alzheimer's disease. Cognitive Development Proper axonal connections are essential for cognitive functions, such as learning and memory. Motor Control Accurate axonal guidance is crucial for coordinating muscle movement and maintaining balance. Sensory Perception Axon pathways convey sensory information from the body to the brain, enabling our senses to perceive the world. Clinical Relevance and Future Directions Understanding axonal guidance and neuronal growth factors has important clinical implications. Research is ongoing to develop therapies for neurological disorders by promoting axonal regeneration and neuronal survival. Neurodegenerative Diseases Spinal Cord Injuries Stroke Targeting growth factors could Enhancing growth factor activity Growth factors could aid in help slow or reverse neuronal loss might promote axonal neuronal survival and recovery in diseases like Alzheimer's and regeneration and functional after stroke, promoting brain Parkinson's. recovery after spinal cord injury. function recovery. Any Questions ??? Feedbacks THANKYOU