lecture 19 development: wiring up the nervous system

Question 1

Axons navigate to
appropriate targets
in how many phases

Answer 1

• Three phases
  “Pathway” selection
  “Target” selection
  “Address” selection

Question 2

“Pathway” selection

Answer 2

E.g.: ipsi or
contralateral at the
optic chiasm

Question 3

“Target” selection

Answer 3

E.g.: lateral
geniculate vs medial
geniculate

Question 4

“Address” selection

Answer 4

E.g.: layers 2, 3, and
5 (ipsilateral)

*innervate the right cell Dendrites of
geniculocortical
cells

Question 5

is the nervous system a random network of synaptically connected neurons?

Answer 5

Non-random specificity in the connections between neurons is evident throughout the nervous system
– Nervous system is partitioned into many separated streams:
motor, sensory, autonomic, enteric
– Topographic maps within each (homunculus)
– Even within one stream high degree of specific (as opposed
to random connections). Take myotatic stretch reflex as an
example- how does it get wired up the right way?

Question 6

Lacrymaria olor

Answer 6

(“tear of a swan”) is single celled free-living organism that looks like a neuron and eats with its extendible “axon” has sophisticated behaviors but obviously no nervous system

Question 7

Axons also seeking things and they often “navigate” over considerable distances to
find what they are looking for

Answer 7

Can be monitored by labeling neurons in living
animals
* For example the retinal ganglion cells in frogs have
to navigate from the retina to the “tectum” – the
equivalent of the superior colliculus in mammals

Question 8

axon growth cone

Answer 8

the navigator that gets
presynaptic neurons to the vicinity of their
postsynaptic partners

*disappears once axon makes a synapse

• Tip of the
  growing axon
• Very
  specialized
  structure
  *seeking behavior

Question 9

Axon guidance cues have various effects…

Answer 9

– Permissive
– Attractive
– Repulsive

Question 10

categories of axon guidance cues

Answer 10

Mechanical e.g.,
“glial tubes” used by
peripheral regenerating axons
– Chemical Cues

Question 11

sites for chemical axon guidance cues

Answer 11

– Substrate: axons grow on substrates e.g.,laminin
is ligand for integrins
on axons
– Other axons (axons
bundle together
“fasciculation” because
of CAMs (cell adhesion
molecules) ; 1st axon is
the “pioneer” )
– Target as beacon

Question 12

Some substrates permit axons to grow

Answer 12

Axon advances along a substrate: usually
“extracellular matrix”
* “In vivo” permissive substrate typically contains the
glycoprotein laminin. Integrins on axons bind to them

Question 13

Some surfaces are repulsive to
axons

Answer 13

• Growth cone “collapse”

Question 14

Axons crossing the midline of spinal cord: both attractive and repulsive cues

Answer 14

Netrin is secreted by ventral
midline “floorplate” spinal
cord cells
* Axons with netrin receptors
“chemotax” to midline
(chemotropism)
* Slit is also secreted by
midline cells
* Axons that approach the
midline are induced to up- regulate the slit receptor
(Robo) on their membranes
* Robo thus prevents axons
that cross the midline from
being attracted by Netrin to
cross again

Question 15

diffusible attractive cues:

Answer 15

chemotropism or chemotaxis
growth cone turning response

Question 16

How do topographic maps form (e.g. retinopy)?

Answer 16

• Roger Sperry worked in Paul
  Weiss’ lab – a proponent of
  physical cues guiding axons
  and “functional molding” of
  random connections (radio
  model)
• Sperry tested this idea with
  the frog visual system
• Will regenerating axons make
  connections that are
  functionally appropriate?
  (radio transmission model vs.
  telegraph wire model) where
  the wires directly connect the
  appropriate partners

Question 17

The Chemoaffinity Hypothesis

Answer 17

Roger Wolcott Sperry pioneered the inception of the Chemoaffinity Hypothesis following his 1960s experiments on the African Clawed Frog. He removed the eye of a frog and rotated it 180°, Sperry then replaced the eye and the visual nervous system repaired itself. However, the frog now had inverted vision.

He found that no matter how much time passed by, the frogs were unable to process the visual information normally and their vision was permanently inversed. That meant that the optic nerve fibers grew back to the exact same point of origin as before the surgery and did not adapt to the rotation of the eye

This result argued that the retinal axons were seeking an address in the tectum that was related to some “identification tag” that allowed them to recognize their appropriate target region- he supposed that the tags were chemical in nature and thus “recognition” molecules

Question 18

• Retino-tectal map:

Answer 18

– Posterior retinal axons project to anterior tectum.
– Anterior retinal axons project to posterior tectum

Question 19

anterior retinal cells

Answer 19

They must cross anterior tectum to get to posterior tectum
* They show no avoidance of anterior tectum and no preference for
posterior tectum
* This kind in vitro stripe “bioassay” led to the identification of a large
number of recognition molecules in the retinotectal pathway- fulfilling
the Sperry chemoaffinity hypothesis

Question 20

Molecular basis of chemoaffinity

Answer 20

Because posterior retina appears to have affinity for anterior tectum, scientists tested the growth of posterior retinal ganglion cells on a
substrate made of cell membranes in alternating stripes from the posterior
and anterior poles of the tectum
* The result was that posterior retinal ganglion cell axons preferentially grew on membranes of anterior
tectum and avoided posterior tectum membranes

Question 21

Ephrin-A gradient

Answer 21

high in posterior tectum & low anterior (Ephrin-A binds to a “receptor” on retinal ganglion cell axons called EphA, a receptor tyrosine kinase- that
is high in posterior and low in anterior retinal ganglion cells)

Question 22

What are the
advantages of gradient cues as
opposed to Lock and Key
chemoaffinity

Answer 22

Need for many fewer molecules than a system where every address is a unique
molecule
* Flexibility

Question 23

Axon guidance

Answer 23

the process by which neurons send out axons to reach the correct target, often following
very precise paths and guided by a number of chemical and physical cues. There are three phases 1. Pathway selection, 2. Target selection and finally 3.
Address selection. Permissive, attractive and repulsive
cues can be provided by the substrate, other axons
and the target to guide the axon at each phase.
Laminin is a glycoprotein that is typically found in the
extracellular matrix around cells and can serve as a
permissive cue. Integrins are proteins found on the
growing axon that bind to laminin, allowing the axon
to continue to grow on that surface. Permissive cues
do not direct the axon, but provide substrate on
which to grow

As the names suggest, attractive and repulsive cues
direct the axon to grow towards (attractive) or away
(repulsive) from the cue. Notably, the commissural
axons of the spinal cord undergo a sequence of attractive and repulsive cues in sending their
axons across the midline.
* Netrin is secreted by ventral midline spinal cord cells
* Axons with netrin receptors “chemotax” to midline
* Slit is also secreted by midline cells
* Axons that approach the midline are induced to up-regulate the slit receptor (Robo)
on their membranes
* Axons expressing the Robo receptor are repelled by Slit.
* Robo thus prevents axons that cross the midline from being attracted by Netrin to
cross again

Question 24

Neurotrophic hypothesis

Answer 24

the idea that the survival of developing neurons depends
on neurotrophins (a family of secreted signaling proteins) that regulate the survival and
morphology/physiology of target neurons through binding to specific receptors on the
target neurons). The developing neurons have an intrinsic pathway towards cell death
unless that pathway is inhibited by trophic factors. Neurotrophins are typcially produced
by the post synaptic targets

Question 25

NGF

Answer 25

nerve growth factor and first identified
neurotrophin. It supports the survival and axon
growth of sensory and sympathetic neurons

Question 26

Axon guidance

Question 27

Growth cone

Answer 27

dynamic structure at the tip of
the developing axon that enables the extension
of the axon and guides its direction. Seeks out
various mechanical (e.g. “glial tubes”) or
chemical cues. When a growth cone
encounters a repulsive cue, you will often
see growth cone “collapse”

Question 28

Sperry Experiment

Answer 28

Experiments in frogs
and rotating the eye which demonstrated
that axons are fated to make very specific
connections with target cells. The basis for
this specificity appears to be gradients of
chemoaffinity agents (factors that axons find
either attractive or repulsive). These
gradients establish topographic maps (e.g.
visual retinotopic maps)

Question 29

Synapse formation

Answer 29

once an axon reaches its target region,
additional cell-cell interactions dictate the synaptic connections.
Changes in both the presynaptic and postsynaptic cells occur to
create a functioning synapse

Question 30

Synaptic rearrangement

Answer 30

The last and longest stage of
development. Molecular cues guide the initial synaptic formation,
yet the refinement and rearrangement often depend on experience
and neuronal activity. The nervous system is particularly
susceptible to experience-dependent remodeling during early
postnatal critical periods (continued in Lecture 20)

Question 31

1. List three phases of decision making for an axon and give an example of each.

Question 32

2. Describe the three types of “cues” an axon receives as it grows to the appropriate targets.

Question 33

3. Understand how gradients of chemoaffinity molecules create a topographic map.