Podcast
Questions and Answers
What is the role of Hox genes in neural development?
What is the role of Hox genes in neural development?
What is the primary function of the growth cone during neuron development?
What is the primary function of the growth cone during neuron development?
Which domain of a polarized neuron is responsible for secreting proteins?
Which domain of a polarized neuron is responsible for secreting proteins?
What type of molecules control Hox gene expression?
What type of molecules control Hox gene expression?
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How does actin contribute to growth cone motility?
How does actin contribute to growth cone motility?
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Which of the following best describes actin treadmilling?
Which of the following best describes actin treadmilling?
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What is the role of the PAR family in neuronal polarization?
What is the role of the PAR family in neuronal polarization?
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What happens to actin at the plus and minus ends during treadmilling?
What happens to actin at the plus and minus ends during treadmilling?
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What is the main structural component of the cytoskeleton that drives the motility of growth cones?
What is the main structural component of the cytoskeleton that drives the motility of growth cones?
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What are lamellipodia and filopodia associated with in growth cones?
What are lamellipodia and filopodia associated with in growth cones?
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What is the primary role of the primitive streak during gastrulation?
What is the primary role of the primitive streak during gastrulation?
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Which of the following is NOT one of the three primary germ layers formed during gastrulation?
Which of the following is NOT one of the three primary germ layers formed during gastrulation?
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What is the main focus of the Developmental Origins of Health and Disease (DOHaD) concept?
What is the main focus of the Developmental Origins of Health and Disease (DOHaD) concept?
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Which process is involved in the differentiation of the nervous system from the ectoderm?
Which process is involved in the differentiation of the nervous system from the ectoderm?
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What is neural patterning primarily responsible for in nervous system development?
What is neural patterning primarily responsible for in nervous system development?
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Which of the following best describes synapse formation in neural development?
Which of the following best describes synapse formation in neural development?
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Which segment of the brain differentiates into the hindbrain?
Which segment of the brain differentiates into the hindbrain?
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What role do netrins play in commissural neuron migration?
What role do netrins play in commissural neuron migration?
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Which molecule is specifically noted for repelling axons while attracting dendrites?
Which molecule is specifically noted for repelling axons while attracting dendrites?
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What is the primary purpose of dendritic tiling?
What is the primary purpose of dendritic tiling?
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Which molecules are implicated in local recognition during synapse formation?
Which molecules are implicated in local recognition during synapse formation?
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What is the main function of DSCAM genes in dendritic growth?
What is the main function of DSCAM genes in dendritic growth?
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What role do EphA7 and Ephrin A5 play in neural tube development?
What role do EphA7 and Ephrin A5 play in neural tube development?
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What is the primary consequence of knocking out EphA7 and Ephrin A5?
What is the primary consequence of knocking out EphA7 and Ephrin A5?
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Which type of protein are Ephrins and Eph receptors classified as?
Which type of protein are Ephrins and Eph receptors classified as?
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What process is indicated by the presence of alpha fetoprotein in the amniotic fluid?
What process is indicated by the presence of alpha fetoprotein in the amniotic fluid?
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What occurs during secondary neurulation?
What occurs during secondary neurulation?
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What is NOT a technique used to investigate RNA expression in a human blood sample?
What is NOT a technique used to investigate RNA expression in a human blood sample?
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In the context of intracellular connections, what is the function of N-CAM?
In the context of intracellular connections, what is the function of N-CAM?
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Which of the following is a crucial step in the process of secondary neurulation?
Which of the following is a crucial step in the process of secondary neurulation?
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What is the significance of Eph receptors in the neural folds?
What is the significance of Eph receptors in the neural folds?
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What are the subunits of microtubules called?
What are the subunits of microtubules called?
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What do the lateral contacts between monomers of the same type in microtubules create?
What do the lateral contacts between monomers of the same type in microtubules create?
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What characterizes the dynamic instability of microtubules?
What characterizes the dynamic instability of microtubules?
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What occurs during a catastrophe in microtubule dynamics?
What occurs during a catastrophe in microtubule dynamics?
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Which proteins are known for moving molecules up and down neuronal processes?
Which proteins are known for moving molecules up and down neuronal processes?
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How are axon guidance signals transmitted?
How are axon guidance signals transmitted?
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Which of the following functions as integrin receptors in axon guidance?
Which of the following functions as integrin receptors in axon guidance?
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What type of structure does a microtubule primarily possess?
What type of structure does a microtubule primarily possess?
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What is needed for the rescue phase in microtubule dynamics?
What is needed for the rescue phase in microtubule dynamics?
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What role do microtubule-associated proteins (MAPs) play in neurons?
What role do microtubule-associated proteins (MAPs) play in neurons?
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Study Notes
Learning Objectives
- Review the concept of Gastrulation
- Describe neural development
- Explain neural plate and tube formation
- Understand nervous system patterning
- Describe synapse formation
Why is Neurodevelopment Important?
- Early gestation (0-3 months/E0-7)
- Mid-gestation (3-6 months/E7-14)
- Late gestation (6-9 months/E14-21)
- Neonate (0-1 year/P0-14)
- Toddler/Weanling (1-4 years / P20-25)
- Adulthood (18 years+/P60+)
- Synapse formation
- Neuronal progenitor
- Neural stem cell
- Neuron production
- Astrocyte and oligodendrocyte production & maturation
- Glial progenitor
- Macrophage
- Microglia production & maturation
- Epigenetic effects of early life stress (ELS) on cellular programming
- Maternal factors via placenta/lactation
- Direct effects
- Endocrine stress axis
- Infectious agents
- Inflammatory diets
Contents
- Neural development
- Research methods in neural development
- Development of ectoderm
- Primary neurulation
- Secondary neurulation
- Neural crest
- Failure of neural crest cells (NCC)
- Histogenesis within the CNS
- Patterning of the neural tube
- Cell lineage of CNS
- Neuronal migration in the CNS
- Early brain development
- Differentiation of the forebrain
- Differentiation of the midbrain
- Differentiation of the hindbrain
- Differentiation of the spinal cord
- Construction of neural circuits
- Neuronal polarization
- Synapse formation
- Neurovascular diseases
Review of Gastrulation
- Gastrulation begins with the primitive streak
- Primitive streak→ cells in the epiblast layer migrate
- Formation of three germ layers:
- Ectoderm: skin and nervous system
- Mesoderm: bones and muscle
- Endoderm: internal organs
Gastrulation Movements
- Gastrulation in the chick.
- Fluorescently labelled cells along the primitive streak allow movement of cells during gastrulation
- Red cells (anterior) move laterally and anteriorly
- Green cells (posterior) move laterally
Formation of the Notochord
- Notochord→ cylinder of mesodermal cells
- Functions:
- Positioned centrally in the embryo with respect to both the dorsal-ventral (DV) and left-right (LR) axes
- Send signals to the ectoderm causing cells to differentiate (thicken the ectoderm→ neuroectodermal precursor cells)
Neural Development
- From the first 2 weeks to stem cell regeneration of adult neural tissue
- The nervous system develops:
- from the anterior to the posterior
- later from the inside towards the outside
- The nervous tissue develops in conjunction with other tissues
Research Methods to Study Neural Development
- Microdissection and transplantation
- Add protein-soaked beads
- Add cells expressing protein
- Overexpression: cre-lox and introduction of plasmids, using viruses and electroporation
- Controlled expression
- Knock down: RNAi
- Knock out: CRISPR electroporation and use of plasmids
- Checking gene transcription and expression: RT-PCR, PCR, In Situ Hybridisation, Microarray, Immunohistochemistry, Immunocytochemistry, Western Blotting, Histology, In vitro and in vivo imaging
- Cell culture and tracking of GFP expression
Primary Neurulation
- Formation of the neural plate
- Neural plate midline ectoderms containing thicker cells
- Border of the neural plate (neural crest)→ BMP
- Ectodermal→ subdivided into two developmental lineages: neural and non-neural
- Shaping the neural plate:
- Narrower and longer
- Cells migrate along midline
- And become longer along the anteroposterior axis and narrower laterally
- Lateral folding of the neural plate
- Elevation of each side of the neural plate
- Formation of hinge points
- Dorsolateral hinge points and medial hinge points
- Neural tube closure:
- Fusion of the two folds
- Extension of lamellipodia and filopodia
- Cells interlock and fuse
- Neural crest begins to separate from the neural tube
- Detachment from the ectodermal layer
Secondary Neurulation
- Caudal to posterior neuropore (evolved in vertebrates with longer tails/no prominent in humans)
- Formation of a rod-like condensation of mesenchymal cells
- Occurs via cell migration and condensation
- Mesenchymal cells change and become epidermal in identity
- Attach to neural tube and cavity becomes continuous
Neural Crest
- From the prosencephalon to the future sacral region
- Non-neural lineage from the ectoderm
- Cells located along the lateral margins of the neural plate
- Migrate to other positions around the body
Cranial crest subdivision
- Migrate along the dorsolateral pathways between the somites and the ectoderm
- Neural crest cells migrate from the mesencephalon into the head and from rhombomeres: r1 and r2→ first pharyngeal arch, r4→ second arch, r6 and r7→ third arch
- Circumpharyngeal neural crest
- Transition between cranial and trunk neural crest
- Cardiac crest
- Separate the outflow tract of the heart into aortic and pulmonary segments
Neural Crest Cell Migration
- Images of neural crest cells in chick embryos moving away from the neural tube and into pharyngeal pouches
Failure of NCC migration
- Intestinal Aganglionosis (Hirschsprung's Disease or Megacolon)
- Genetic disease
- Nerves are missing in some areas of the digestive system
- Surgery removing affected areas
- Neurofibromatosis
- Genetic disease
- Tumors grows in the nervous system
- 3 types
- Surgical removal of the tumors
- Neuroblastoma
- Genetic mutation
- 100 children/year in UK
- Adrenal gland tumours or along the spinal cord.
Histogenesis within the Central Nervous System
- Proliferation within the neural tube
- Neuroepithelial cells
- High degree of mitotic activity within the neural tube
- DNA synthesis → external limiting membrane
- Orientation of the mitotic spindle predicts the fate of the daughter cells
- Metaphase plate perpendicular to inner surface of neural tube→ cell migrate in tandem back toward outer side
- Daughter cell closer to the inner surface migrates away
- Other daughter cell progresses to the next stage in the neural lineage
Patterning of the neural tube
- Biological process by which cells acquire distinct identities
- Controlled by signaling gradients along the axis of development
- Dorsal-ventral axis
- Compartments of neural progenitor cells lead to distinct classes of neurons
- Roof plate:
- Dorsal signal→ bone morphogenetic proteins (BMPs)
- Commissural neurons, 2° sensory neurons, associated interneurons, 1 sensory neurons from Neural Crest
- Floor plate:
- Ventral signal→ Sonic Hedgehog
- Motor neurons, ventral roots of spinal cord, associated interneurons
- SHH stimulates formation of the MHP (median hinge point)
Rostral-caudal axis
- Signals from anterior visceral endoderm, prechordal plate, and notochord
- Otx-2 in the future forebrain and midbrain regions
- Gbx-2 in the hindbrain and spinal cord
- Later in development:
- Rostral neural tube forms 3 primary brain vesicles - prosencephalon (forebrain) - mesencephalon (midbrain) - rhombencephalon (hindbrain)
- Caudal spinal cord
Cell Lineages of the Central Nervous System
- Neuroepithelial stem cells
- Radial precursor cells
- Radial glial cells
- Neurogenesis
- One daughter cell remains as radial precursor cell
- Other, radial glial cell, become neuroblast and ultimately a neuron
- Two neuroblasts
Neuronal migration in the CNS
- Neuroblast migrate toward the periphery by following set patterns
- Radial glial cells→ post-mitotic neurons wrap themselves around radial glial cells and use them as guides for their migrations
- Inside-out pattern➔ cortex, Out-inside pattern➔ cerebellum
Synapse formation
- Restrictions in synapse formation
- CNS neurons don't synapse with glia
- PNS neurons don't synapse with connective cells
- Overlapping subset of molecules that regulate general aspects of synapse formation
- Secreted signals implicated in this process→ growth factors and neurotransmitters
Molecular Mechanism of Synapse Formation
- Local recognition pre and post synaptic
- Cadherin and protocadherin
- Accumulation of synaptic vesicles
- Adhesive signalling
- SynCAM, Neurexin, Neuroligin, Neuregulin
- Differentiation of active zone and postsynaptic density
- Clustering postsynaptic receptors
- Localizing molecules
- Synaptic vesicles (neurexin)
- Voltage-gated Ca2+ channels (neurexin)
- Neurotransmitters receptors (neuroligin)
Regulation of Neuronal Connections
- Trophic interaction→ dependency between neurons and their target
- Neurotrophic factors→ regulate differentiation, growth and survival in nearby cells
- Production of initial surplus of nerve cells
- Survival depends on location, species, and activity→ large numbers of neurons die because they do not make synapses (apoptosis)
- Modulating neuronal connections
- Convergence→ number of inputs to a target cell
- Divergence→ number of connections made by a neuron
- Polyneuronal innervation (embryonic stage)
- Synapse elimination→ reduction in number of axonal inputs to the target cell
- Synapse contacts increase in PNS and CNS along the life
Neurotrophins and Disease
- Neurotrophic factors have been liked with postnatal disease
- Huntington's Disease
- Decreased Brain Derived Neurotrophic Factor (BDNF)
- Death of striatal neurons
- Involuntary muscle movements and cognitive problems
- Parkinson's
- Decreased Glial Derived Neurotrophic Factor (GDNF) and BDNF?
- GDNF promotes survival of dopaminergic neurons
- BDNF required for neural response to dopamine
Axon Guidance
- Presence of specific “cues” (proteins) that cause the growth cone to move in a particular direction
- Initiate intracellular signalling → alter the cytoskeleton
- EM molecules and integrins receptors
- Cell adhesion molecules
- Cadherins
- Ephrins
CAMs and Cadherins
- Found on growth cones as well as on surrounding cells and target
- Dual function→ ligands and receptors
- Cadherins→ determinate the final target selection
- Signal transduction
- CAMs cytoplasmatic kinases pathway
- Cadherins→ β-catenin pathway
Ephrins
- Tyrosine kinase receptors (Eph)
- Role in synaptogenesis and the growing of the immature axons
- Depending on the nature of signal transduction
- Growth-promoting, Growth-limiting
Chemoattraction and Chemorepulsion
- How do the axons choose the appropriate target?
- Chemoattractants→ netrins
- High homology with EMC (laminins)
- Receptors→ DCC, Unc5
- Chemorepellents→ CNS myelin and semaphorins
- Bound to the cell surface or ECM
- Receptors plexin, neuropilin
- Commissural Neuron Migration:
- Commissural Neurons migrate across the midline
- Netrins
- Chemoattractive signal in the spinal cord ventral midline
- Guide the growth of spinothalamic axons
- Localized in the floorplate of neural tube
- Slit and Robo prevent the axon returning back
Dendritic Growth
- Maintenance, guided growth, and local branching of dendrites
- Chemoattractive and chemorepellant signaling
- Sema3A repels axons of developing neurons
- Attract for the dendrites of the same cells (via neuropilin recptors)
- Notch and BDNF act as a positive signal for cortical dendritic branching
Dendritic Tiling
- Modulation of dendritic growth where each dendritic arbor occupies appropriate space
- Avoiding dendrites from the same neuron
- Adequate coverage for a particular region
- DSCAM genes→ dual repulsion
- Responding to molecular signals from its own dendrites and other neurons
Molecular Mechanism of Growth Cone Motility
- Controlled rearrangement of the cytoskeleton
- Actin → changes in shape
- Microtubule → elongation of the axon
- ATP-dependent
Actin Treadmilling
- 375 amino acid polypeptide carrying a associated molecule of ATP
- Actin subunits assemble head-to-tail to create flexible polar filaments
- The polymer maintains constant length
- Two ends of an actin filament→ Plus end (faster dynamics) and minus end (slower dynamics)
Actin Binding Proteins
- Regulate polymerization and depolymerization
- Mediate assembly and membrane anchoring of actin filaments
- Found in the inner surface of the growth cone plasma membrane
Molecular Mechanisms of Axon Guidance
- Presence of specific “cues” (proteins) that cause the growth cone to move in a particular direction
- Initiate intracellular signaling → alter the cytoskeleton
- EM molecules and integrins receptors
- Cell adhesion molecules
- Cadherins
- Ephrins
CAMs and Cadherins
- Found on growth cones as well as on surrounding cells and target
- Dual function→ ligands and receptors
- Cadherins→ determinate the final target selection
- Signal transduction
- CAMs cytoplasmatic kinases pathway
- Cadherins→ β-catenin pathway
Ephrins
- Tyrosine kinase receptors (Eph)
- Role in synaptogenesis and the growing of the immature axons
- Depending on the nature of signal transduction
- Growth promoting
- Growth limiting
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Description
This quiz explores the intricate processes involved in neurodevelopment, focusing on gastrulation and subsequent neural development stages. Key topics include the formation of the neural plate and tube, nervious system patterning, and synapse formation, as well as the impact of early life factors on development. Test your understanding of these vital concepts in the timeline of gestation and beyond.
