Lecture 27: Neural Development

Question 1

Phases of Neural Development

Answer 1

• Phase 1
  
  • Different cells types (neurons, glia, muscle cells) develop independently at widely separate locations in embryo according to local program and are unconnected
• Phase 2
  
  • Axons and dendrites grow out along specific routes setting up a provisional but orderly network of connections between various parts of the system
• Phase 3
  
  • Continues into adult life, connections are adjusted and refined through interactions with distant regions via electric signal

Question 2

Origin of the Nervous System

Answer 2

• Neurons are produced in association with glial cells (provide supporting framework and nutrition)
• Both cell types develop from ectoderm from a common precursor
• CNS (brain, spinal cord, and retina) derived from neural tube
• PNS (nerves, sensory neurons) derived from neural crest

Question 3

Formation of the Neural Tube

Answer 3

• Neural tube derived from a single layered epithelium
• Starts with a neural groove on the dorsal side fo embryo
• Gradually deepens as neural folds become elevated
• Ultimately the folds meet and coalesce in the middle line and convert the groove into a closed tube, the neural tube
• Center of the neural tube is the neural canal

Question 4

_____ signaling controls differentiation into neurons

Answer 4

• Delta notch (by lateral inhibition)
  
  • Signal proteins secreted from ventral and dorsal side of neural tube act as opposing morphogens, causing neurons at different dorso-ventral positions to express different gene regulatory proteins

Question 5

Neural crest cells

Answer 5

• Originate at the dorsal end of the neural tube
• Migrate extensively during or shortly after closure of the neural tube or neurulation
• Generate several differentiated cell types
  
  • Neurons and glial cells of the PNS
  • Epinephrine-producing cells of the adrenal gland
  • Many of the skeletal and connective tissue components of the head
• Fate of the neural crest cells depends on where they migrate to and settle

Question 6

After final division close to the inner face of the neural tube neurons crawl along

Answer 6

radial glial cells

Question 7

Development of the spinal cord

Answer 7

• Differences in gene expression modulate the characteristics of neurons and the connections they make
• Dorsal neurons of spinal cord receive and relay sensory information from sensory neurons located in the periphery of the body
• Ventral clusters of spinal cord neurons develop as motor neurons send out long axons to connect with specific subset of muscles
• Intermediate location has inter-neurons that connect specific set of nerve cells to each other

Question 8

Tip of axon/dendrite has an irregular, spiky enlargment called _____, which crawls though surrounding tissue, trailing the axon or dendrite behind

Answer 8

growth cone

Question 9

Growth Cones

Answer 9

• Spiky enlargment at the tip of axon/dendrite
• crawls through surrounding tissue, trailing the axon or dendrite behind
• behavior is dictated by its cytoskeletal machinery
• they throw out (project) Filopodia (one-dimension) and lamelopodia (two-dimensional)
• Monomeric GTPases Rho and Rac control the assembly/disassembly of actin filaments, which control movement of growth cone
  
  • Withdraw from unfavorable surfaces and steers cell towards favorable ones where it persists for longer time

Question 10

________ control the assembly/disassembly of actin filaments, which control movement of growth cone

Answer 10

Monomeric GTPases (Rho and Rac)

Question 11

Growth cones travel towards target along predictable route, exploiting two major cues to find the way: what are the cues?

Answer 11

• Extracellular matrix environment sensed by receptors present on membrane
  
  • (example: the matrix molecule laminin favors axon outgrowth while as chondroitin sulfate porteoglycans discourages it
• chemotactic factors released by neighboring cells
  
  • May be attactive or repulsive
  • Examples
    
    • Netrin (attractant)
    • Slit (repellent)
    • Semaphorin (repellent)

Question 12

What is meant by contact guidance (this is in terms of migration of growth cones)

Answer 12

• Growth cones oftne follow a path taken by other cells
• (note that this is why nerve fibers are usually found in bundles)
  *

Question 13

How do the following ECM molecules affect Neuronal growth:

• Laminin?
• Chondroitin Sulfate Proteoglycans ?

Answer 13

• Laminin
  
  • favor axonal outgrowth
• Chondroitin sulfate proteoglycans
  
  • Inhinbit growth

Question 14

Growth cone outgrowth is mediated by homophilic cell adhesions (this makes sense because it is pulled forward by filopodia and lamelopodia) what are the two important classes of homophilic cell adhesion molecules?

Answer 14

• Immunoglobulin superfamily
• Cadherin family

Question 15

Mechanism of Commissural Neuron Guidance

Answer 15

• First stage:
  
  • Netrin (an attractent) is secreted by floor plate
  • Netrin binds to its receptor (DCC) thus causing opening of transient receptor potential C (TRPC) channels
    
    • this allows entry of extracellular calcium
    • Leads to activation of machinery for extension of filopodia and movement of growth cone (toward middle)
• (note that non-commissural neurons don’t have receptors for Nectrin and thus don’t move toward the floorplate/midline)
• But why do commimisural neurons cross midline?
  
  • The answer lies in a change in the responsiveness of the growth cones during the journey
  • As the growth cones cross the midline, they lose sensitivity to Netrin and become Sensitive to Slit
• Slit
  
  • ​secreted by midline cells
  • Slit receptor Roundabout present on commissural neurons
  • Slit repels growth cones and blocks entry back to midline (thus not allowing them to cross back over)
• Growh cones become sensitive to another repulsive sinal called semaphorin, Which comes from the wall of the neural tube
  
  • with Slit keep growth of neuron in a narrow track ​

Question 16

Answer 16

Question 17

What is the first portotypical neurotrophic factor to be identified

Answer 17

• Nerve Growth Factor (NGF)

Question 18

Neurotrophic factors, such as Nerve growth factor, belong to the family of _____

Answer 18

• neurotrophins

Question 19

Nerve growth factor receptor

Answer 19

Tyrosine Kinase (TrkA)

Question 20

Effects/functions of Nerve Growth Factor (NGF), include both long term and short term effects

Answer 20

• Overall
  
  • Promotes survival of specific sensory neurons and sympathetic neurons
• Short term: (growth)
  
  • Effect on growth cone and neurite extension
  • Effect is local, direct rapid, and independent of communication with cell body
• Long term: (survival)
  
  • Effect on cell Survival
  • Mediated by its receptor, uptake into cells via endocytosis and stimulation of downstream signaling pathways

Question 21

Activity-dependent Synaptic Remodeling

Answer 21

• E.G. Retinal/Tactal Neurons
• depends on electrical activity and synaptic signaling
• Each axon branche snad makes multiple synapes with target cells
• Network subsequently trimmed (of weak synapses) by elimination of synapses and retraction of axon branches.
• Accompanied by sprouting of axons to develop denser distribution of synapses that survive

Question 22

• Synaptic remodeling is dependent upon what 2 rules that create spatial order:

Answer 22

• axons from cells in different regions of retina (which are excited at different times) compete for tectal neurons.
• Axons form neighboring sites, which are excited at same time cooperate/collaborate to retain and strengthen synapses with tectal neurons

Question 23

Explain Adult Memory and the phrase ‘neurons that fire together wire together’

Answer 23

• Synapses are strengthened by external events that cause 2 or more neurons to be activated at the same time
• Entry of Calcium through the glutamate receptor (NMDA Receptor) triggers lasting change in synaptic strength
  
  • corresponding change in physical structure of synapse
• Individual dendritic spines remodeled, new spines appear with electrical stimulation