Neurogenesis

What is the definition of axon guidance?

The process by which neurons send out axons to reach the correct targets during neuronal development.

Which dynamic structure is located at the very tip of the growing axon and drives navigation?

The neuronal growth cone.

What are the three primary functions of the growth cone?

It acts as a sensory organelle, makes directional decisions, and provides the physical force to pull the axon forward.

Where are highly dynamic actin filaments packed within the developing neuron?

In the growth cone.

Where are stable microtubules primarily found within a developing neuron to provide structural support?

In the cell body and the axon trailing behind the growth cone.

What are the four classes of guidance cues received by the growth cone?

Long-range chemoattraction, long-range chemorepulsion, short-range contact attractants, and short-range contact repellents.

What is defined as diffusible signals secreted from a distance that draw the growth cone up a concentration gradient?

Long-Range Attractive (Chemoattraction).

What are long-range repulsive (chemorepulsion) cues?

Diffusible signals that cause the growth cone to grow away from the source or down the gradient.

What are short-range attractive cues (contact attractants)?

Non-diffusible, membrane-bound, or extracellular matrix (ECM) molecules that the growth cone physically grabs and grows along.

What effect do short-range repulsive cues (contact repellents) have on the growth cone?

They are non-diffusible molecules that cause the growth cone to retract or turn away upon physical contact.

Which RhoGAP GTPases are mentioned as being involved in integrating cues for receptor signaling?

Rac, Rho, and Cdc42.

What are the names of the sensory fingers and webbing structures built by actin to steer the growth cone?

Filopodia (sensory fingers) and lamellipodia (webbing).

Name the three families of diffusible signals involved in axonal guidance.

Netrin/Slit family, Semaphorins, and morphogens.

What are Netrins and through which receptors do they typically signal?

Netrins are diffusible ligands that signal through receptors like DCC (Deleted in Colorectal Cancer) and Unc5.

What is the crucial rule regarding whether a guidance cue is attractive or repulsive?

A cue is not inherently attractive or repulsive; the response depends entirely on the receptors expressed by the specific neuron.

Why do dorsal commissural interneurons project axons ventrally toward the floor plate?

They are attracted to Netrin-1 secreted at the floor plate.

Which specific neurons project dorsally away from the floor plate in response to Netrin-1?

Trochlear motor neurons.

Where are trochlear motor neurons born?

In the ventral neural tube at the mid/hindbrain.

What evidence of evolutionary redundancy is seen in Netrin-1 mutant mice?

Commissural axons still head ventrally because Netrin-2 is expressed broadly in the ventral spinal cord.

What is Collapsin in the context of axon guidance?

A specific type of secreted, diffusible Semaphorin (III) that acts as a long-range chemorepellent.

Besides diffusible forms, what are the other states of Semaphorins?

Transmembrane or membrane-tethered.

How do Semaphorins assist in channeling sensory neurons?

They repel dorsal root ganglion (DRG) sensory neurons away from the ventral spinal cord and dermomyotome.

What occurs during the process of growth cone collapse?

Sensory attachments weaken and the cone snaps backward due to contact with an incompatible membrane-bound Semaphorin.

What is the primary role of Semaphorins during nervous system development?

They primarily act as repulsive cues.

Where do dorsal commissural neurons project their axons relative to the midline?

They project ventrally to the floor plate, cross the midline once, and then migrate anteriorly.

What happens to Drosophila roundabout (Robo) mutants during midline crossing?

They get trapped endlessly recrossing the midline.

How do mammalian axons ensure they cross the midline only once?

They radically change their receptor expression as they cross the floor plate.

Which receptor allows pre-crossing commissural axons to follow the Netrin-1 gradient?

The DCC receptor.

Why are approaching axons initially deaf to the Slit repellent secreted by the floor plate?

They express a non-functional version of the Slit receptor known as Robo3.1.

How do commissural axons temporarily avoid Semaphorins before crossing the midline?

They use enzymes to proteolytically cleave Plexin A, a core component of the Semaphorin receptor.

What change occurs to DCC expression after the axon crosses the floor plate?

The growth cone turns off expression of DCC.

Which receptor is switched on after the axon crosses the floor plate to regain Slit sensitivity?

Robo3.2.

What is the function of Robo3.2 compared to Robo3.1?

Robo3.2 is a fully functional receptor that makes the axon highly sensitive to Slit.

What happens to Plexin A once the axon has crossed the floor plate?

Proteolytic cleavage halts, stabilizing Plexin A on the membrane so the neuron regains sensitivity to Semaphorin.

Name three types of morphogens that function in axonal guidance.

Shh, BMPs, and Wnts.

What molecule acts as a directional chemoattractant for axons to orient anteriorly after crossing the midline?

Wnt4.

What is the receptor for the morphogen Wnt4?

Frizzled3.

What happens to axons if the Frizzled3 receptor is knocked out?

Axons cross the midline successfully but wander aimlessly, unable to orient anteriorly.

What is the specific concentration difference sensitivity of a growth cone?

$0.1\%$.

What does a $0.1\%$ sensitivity indicate about the growth cone's capabilities?

It can detect a minuscule difference in the concentration of a guidance molecule from its leading edge to its trailing edge.

How is the process of axons bundling together and following established pathways known?

Fasciculation.

What family of transmembrane proteins allows cells to physically bind to one another?

Cell Adhesion Molecules (CAMs).

To which superfamily do N-CAM and Ng-CAM belong?

The Ig (immunoglobulin) Superfamily.

What type of binding is used by N-CAM (Neural CAM)?

Homophilic binding (N-CAM on one cell binds to N-CAM on another).

What is the specific function of Ng-CAM (Neural-glial CAM), also known as L1?

It mediates interactions between axons and myelinating glial cells.

Which glial cells in the peripheral nervous system interact with Ng-CAM?

Schwann cells.

Which glial cells in the central nervous system interact with Ng-CAM?

Oligodendrocytes.

What is the unique requirement for Cadherins, such as N-cadherin, to stick cells together?

They are dependent on Calcium ($Ca^{2+}$) to function.

What does the acronym MASA stand for in MASA syndrome?

Mental retardation, Aphasia, Shuffling gait, and Adducted thumb.

In the context of MASA syndrome, what is the definition of Aphasia?

A defect in the generation and understanding of speech related to information processing, not motor control.

What is the underlying cause of MASA syndrome?

A mutation in Ng-CAM (L1).

Why does a mutation in the widely expressed Ng-CAM cause specific symptoms rather than widespread failure?

Redundancy; most pathways are guided by multiple overlapping cues.

What are vulnerability points in the developing nervous system?

Specific locations where there are no redundant backup cues, making a specific molecule like Ng-CAM absolutely essential.

What do growth cones express to physically grip extracellular matrix (ECM) proteins?

Integrin dimers.

Name four ECM proteins mentioned in the text.

Collagen, tenascin, laminin, and fibronectin.

What is a stripe assay?

An experiment offering alternating tracks of different proteins, like Collagen IV and Laminin, to observe axonal preference.

In a stripe assay with Collagen IV and Laminin, which track do axons prefer?

Laminin stripes.

What does the axonal preference in a stripe assay demonstrate?

Navigation is an active, continuous integration of environmental signals where the growth cone evaluates relative preferences.

What provides the physical force to pull the axon forward?

The neuronal growth cone.

What is the function of Netrin-1 when it is interpreted as a chemorepellent?

It causes the growth cone to project away from the source, as seen in trochlear motor neurons.

What molecule is identified as the ligand for DCC?

Netrin-1.

What molecules mediate the fasciculation of neurons into bundles?

CAM (Cell Adhesion Molecule) interactions.

Is N-cadherin binding heterophilic or homophilic?

Homophilic.

What happens to the sensitivity to Netrin-1 after an axon crosses the midline?

Sensitivity is lost because DCC expression is turned off.

Which molecule is described as a secreted semaphorin that channels migrating axons?

Collapsin.

Which system's connection establishment is the central focus of the lecture notes?

The CNS (Central Nervous System).

What ensures that axons never return once they cross the floor plate?

The rapid and radical shift in receptor expression.

What makes the growth cone a sensory organelle?

Its ability to evaluate the environment and detect subtle gradients.

True or False: Long-range signals are always attractive.

False (they can be chemoattractant or chemorepellent).

Which type of binding describes an N-CAM binding to different molecules on other cells?

Heterophilic CAM interactions (dependent on the context of midline crossing).

Which family of molecules include Netrins and Slits?

The Netrin/Slit family (diffusible signals).

What is the term for the webbing structures created by the growth cone?

Lamellipodia.

What is a synonym for Ng-CAM?

L1.

What allows the growth cone to follow subtlegradients over vast distances?

Extreme sensitivity to concentration differences (up to $0.1\%$).

Which specific structure secretes Slit and Netrin-1 at the midline?

The floor plate.

How do growth cones exit the retina and enter the optic nerve?

They are pushed away from the retina by the repellent Slit and pulled toward the base of the optic nerve by the attractant Netrin.

What role do Semaphorins play as axons travel along the optic nerve?

They act like guardrails to constrain the axons within the nerve pathway.

What decision must axons make at the optic chiasm?

They must choose whether to stay on the same side (ipsilateral) or cross over to the other side of the brain (contralateral).

Which receptor is expressed by ipsilateral growth cones at the optic chiasm?

EphB1.

Which ligand at the optic chiasm repels EphB1-expressing axons?

Ephrin B2.

Why do contralateral axons ignore the Ephrin B2 repellent at the chiasm?

They do not express the EphB1 receptor.

Which receptor and cell adhesion molecule are expressed by contralateral axons?

Plexin A1 and NrCAM.

Which Semaphorin is expressed at the optic chiasm to interact with contralateral axons?

Sema6D.

How does the presence of NrCAM change the response of contralateral axons to Sema6D?

It contextually transforms the Sema6D repellent into a powerful attractant, pulling axons across the chiasm.

What protein do contralateral axons physically grip to migrate along the forebrain toward the tectum?

Laminin, which is an extracellular matrix (ECM) protein.

What happens to the sensitivity of axons toward Semaphorins after they cross the midline and reach the forebrain?

They turn off NrCAM, causing Semaphorins to return to being repellents that, along with Slit, keep them channeled on the correct path.

How do axons successfully navigate long, complex distances?

They break the journey into short, independent segments and dynamically swap receptors at different waypoints.

Where do retinal ganglion cells project in frogs?

Directly to the optic tectum in the dorsal forebrain.

In mammals, what are the two main projection targets for retinal neurons?

The lateral geniculate nucleus (LGN) of the thalamus and the superior colliculus (the anatomical equivalent of the tectum).

What is the definition of a topographic map?

A $2$-dimensional representation in the brain that strictly preserves the spatial topology of incoming neurons, maintaining a point-to-point correspondence.

How does the nasal-temporal axis of the retina map onto the tectum?

It maps directly onto the anterior-posterior axis of the tectum.

Which region of the retina projects to the anterior tectum?

The temporal side.

Which region of the retina projects to the posterior tectum?

The nasal side.

In Roger Sperry's experiment, what happened to existing axons after the optic nerve was severed?

The existing axons naturally degenerated.

What occurred when Sperry rotated the frog's eye $180^{\circ}$?

The regenerating retinal neurons navigated back to their exact original target sites in the tectum, ignoring the new orientation.

Why was the frog's vision permanently inverted after the eye rotation experiment?

The eye was physically upside down and backward, but the wiring to the brain remained exactly the same as before the rotation.

What did the frog's hunting behavior after eye rotation prove about regenerating axons?

They followed strict positional instructions rather than adapting to their new functional reality.

What occurs initially if the posterior half of the tectum is removed (Map Compression)?

The temporal axons hit the anterior tectum normally, but the nasal axons go as far as they can until they hit a dead end.

How does the map regulate after the partial removal of the tectum?

The projecting axons compress and redistribute themselves to recreate the full map pattern on the remaining smaller piece of tissue.

What is Map Expansion in the context of removing half of the retina?

If the nasal retina is removed, the remaining temporal axons initially project only to the anterior tectum but eventually expand to cover the entire tectum.