Unit 4 - Lecture 19

What are the four proteins that cue for axon migration as well as regulate neural crest cell migration?

1. Ephrins
2. Semaphorins
3. Netrins
4. Slit

How are these proteins activated?

By particular Hox and Lim proteins along the body axis.

Ephrins, semaphorins, netrins, and Slit proteins can act to:

A) Promote attraction

B) Repulsion attraction

C) Passive

D) All of the above

D) All of the above, depending on the nature of the receptors present on the axon. 

The receptor present on an axon is dependent on what?

* The type of cell
* The time

**Ephrins**

membrane-anchored or transmembrane proteins that are recognized by the **Eph** receptor.

**Semaphorins**

transmembrane and secreted proteins that are recognized by the **neuropilin** receptors.

Ephrins and Semaphoring only act in repulsion (T/F).

False. in most cases they act in repulsion, but under some circumstances some can act in attraction.

**Netrins**

key diffusible **chemotactic** cues for neuron guidance.

Netrin-1 is recognized by two receptors found in axon growth cones, called:

A) Notch, Pax6

B) FGF8, BMP

C) DCC, DSCAM

C) **DCC** and **DSCAM**

Netrins usually are repulsive but can switch to attractive (T/F). 

False. Netrins usually are attractive but can switch to repulsive. 

Why would Netrins switch from attractive to repulsive?

When the axon reaches its intended destination, preventing further migration.

**Slit**

diffusible proteins generally acting in repulsion (chemorepulsion).

What is the receptor family for Slit?

**Robo**

Robo1/2

repulses neurons. Downregulation (-) allows **commissural neurons** to cross the body’s midline.

Robo3.1

opposite role of Robo1/2, promoting the crossing of the of the midline.

What happens when mutations are found in Robo3?

Humans are unable to coordinate eye movements.

Once a neuron reaches a group of cells in which lie its targets, it finds its specific target cells by responding to additional chemotactic peptides, two called?

* **Endothelins**
* **Neurotrophins**

Endothelins

secreted by blood vessels that direct migration of certain neural crest cells and certain sympathetic axons that have endothelia receptors.

Endothelins acts to constrict blood vessels in adults (T/F).

True.

Neurotrophins

regulate development, maintenance, and function of vertebrate nervous systems. 

Neurotrophins include five factors, called:

* Nerve growth factor (**NGF**)
* Brain derived neurotrophic factor (**BDNF**)
* Conserved dopamine neurotrophic factor (**CDNF**)
* Neurotrophins 3 (**NT3**)
* Neurotrophins 4/5 (**NT4/5**)

Neurotrophins travel short distances and can also act as attractants or repulsive factors (T/F).

True.

**Synapse**

forms when an axon contacts its target.

Synapse formation involves the thickening of membranes of both cells at the region of contact, this is done by expression of;

* **B2-laminin** that stops further neuronal growth.
* **N-cadherin** to secure neuron-neuron connections.

Neuronal cell death (**apoptosis**) occurs extensively in the central and peripheral nervous system. When does this happen?

When axons have successfully differentiated and extended axons to their correct targets.

Neurotrophin supply is limited (T/F).

True, and different neurotrophins are required to sustain populations of different neurons 

Loss of neurotrophic production in adults can lead to serious diseases including:

* Huntington’s disease
* Parkinson disease

Huntington’s disease

caused by the loss of Huntington protein, resulting in a lack of upregulation of BDNF.

Parkison disease

caused by loss of midbrain dopaminergic neurons, the survival of which may be enhanced by drugs that activate neurotrophic factors. 

**Ecyodermal places**

thickenings of the surface ectoderm that become the rudiments of numerous organs.

**Cranial sensory placodes**

include olfactory (nasal), auditory (ear), lens (eye) placodes, etc.

Non-sensory placodes

give rise to cutaneous structures such as hair, teeth, feathers, and mammary and sweat glands.

Where are cranial sensory places located?

They are local and transient thickenings of the ectoderm in the head and neck between the prospective neural tube and epidermis. 

Cranial placodes generate most of the peripheral neurons associated with ….

* hearing
* balance
* smell
* taste
* touch
* pain
* temperature 

The lens placed does not form neurons (T/F).

True.

The **pan-placodal region/field** and each region of the specific placodes is specified by placement and timing of:

A) paracrine factor

B) proteins

C) gene expression

D) transcription factors

A) paracrine factor

The pre-pan-placodal field is specified by **Wnt** and **BMP**, how do these factors effect each other?

Wnt induction of BMP, followed by down regulation of Wnt.

**FGF** and **Cerberus**

Downregulate Wnt and BMP. Are active later.

Downregulation of Wnt and BMP leads to what?

Upregulation of **Six1/4** and **Eya1/2**.

**Six1/4** and **Eya1/2** specify what?

Placodes.

Otic-epbranchial development

ear development

How are hearing and balance accomplished?

Through the transformation of mechanical information into electrical stimuli by sensory hair cells in the inner ear.

Sounds waves are captured by the outer ear and channeled to where?

Tympanic membrane (ear drum).

Ear drum vibrations are amplified by the middle ear bones and transferred as waves to the fluid of the … of the inner ear.

**cochlea**

In mammals, the cochlea consists of three separate chambers:

1. Middle fluid-filled chamber
2. Epibranchial placode

Middle fluid-filled chamber

contains the **Organ of Corti**.

Organ of Corti

houses the sensory **hair cells**, which transform the movement of fluid into electrical signals.

Epibranchial placode

forms nearby and gives rise to three cranial nerves:

* Facial (VII)
* Glossopharyngeal (IX)
* Vagys (X)

Together controlling facial expression, sense of taste, speech, swallowing, heartbeat, sweating, peristalsis, etc.

In the first step of otic specification, **Fgf** form head mesoderm specifying which region?

A) Posterior cocleovestibular ganglion

B) Anterior optic cup

C) Anterior lens placode

D) Posterior pre-placodal

D) Posterior pre-placodal

The pre-placodal region is soon reinforced by Fgf from the … and ….

**Pharyngeal endoderm** and **neural plate**

Wnt signaling from the neural plate promotes otic identity and represses what at the same time?

**Epibranchial fate**.

Wnt represses epibranchial fate, what factors from the pharyngeal endoderm later promote epibranchial fate?

A) BMP

B) ET

C) FGF8

D) Shh

A) BMP

The otic vesicle forms by three steps:

1. First forming an indentation of the otic placode.
2. Forming an **otic pit**
3. Last forming an **otic cup**.

This pinches off to form the **otic vesicle**.

Otic vesicle is similar to neural tube formation and lens formation (T/F).

True.

Ganglia

sensory neurons formed by placodes.

How are ganglia generated?

By **delamination** of neuroblast cells.

**Otic neuroblast cells** will differentiate into the:

 **cochleovestibular ganglion**.

Cochleovestibular ganglion will form what?

The major neural connection between the brain and inner ear structures.

Optic development

Lens

Using guidance cues from neural crest cells, epibranchial placodes will migrate ventrally or dorsally?

Dorsally.

The lens placed gives rise to the lens of the eye. Does is contribute to nerves as well?

No, unlike other cranial sensory placodes.

Early in development, prechordal plate mesoderm and head endoderm contact head ectoderm, activating …. in ectoderm and giving the head a lens-forming bias.

A) ET

B) Pax6

C) Otx2

D) FGF8

E) Shh

B) Pax6

After pax6 gives the head a lens-forming bias, which structure forms from bulges of the forebrain?

A) Optic nerve.

B) Optic vesicle

C) Optic cup

D) Lens placode

B) **Optic vesicles**

The optic vesicle induces the head ectoderm to form what structure?

A) Optic nerve.

B) Optic vesicle

C) Optic cup

D) Lens placode

D) **Lens placode**.

The optic vesicle bends to form the two layered **optic cup**, which will draw the developing lens into the embryo by:

A) Ingression

B) Invagination

C) Delamination

B) Invagination 

The outer layer (back) of the optic cup forms

A) Pigmented retina

B) Neural retina

A) **Pigmented retina**

The inner cells of the optic cup proliferate and differentiate into what three structures?

1. Photoreceptor neurons
2. Other neurons
3. Glia cells (**neural retina**)

The retinal ganglion cells of the neural retina send electric impulses to the brain. Their axons meet at the base of the eye and become the which structure?

A) Optic nerve.

B) Optic vesicle

C) Optic cup

D) Lens placode

A) Optic nerve.

The inner cells of the optic cells (become neural retina) induce the lens placode to invaginate and become which structure?

A) Optic nerve.

B) Glia cells

C) Lens placode

D) Lens vesicle

D) Lens vesicle

The first step in **eye field** specification of the anterior neural tube is the activation of the transcription factor:

A) ET

B) Pax6

C) Otx2

D) FGF8

E) Shh

C) **Otx2**

Activation of **Otx2** leads to the expression of which factor?

A) ET

B) Pax6

C) Rx

D) FGF8

E) Shh

A) **ET**

What factor does **ET** induce?

A) Otx2

B) Pax6

C) Rx

D) FGF8

E) Shh

C) **Rx** (Retinal homeobox)

What does **Rx** specify?

**Retina**.

Rx induces the major gene that specifies the eye field in the anterior neural plate called:

A) ET

B) Pax6

C) Otx2

D) FGF8

E) Shh

B) **Pax6**

The role of Pax6 is specifying photoreceptor cells and is only seen in humans (T/F).

False, common among lots of animals.

What happens to humans and mice that are heterozygous for *Pax6* mutants.

They have small eyes.

What happens to humans, mice, and *Drosophila* that are homozygous for *Pax6*?

No eyes

**Sonic hedgehog** is secreted by the prechordal plate mesoderm. What is its role in optic development?

Split eye field in two.

Shh secreted by the prechordal plate suppresses …. expression in the center of the neural tube. 

A) ET

B) Pax6

C) Otx2

D) FGF8

E) Rx

B) Pax6

Inhibition or mutation of Shh results in what?

Cyclopia (no split of the eyes)

What happens if shh secretion is in excess?

Loss of eyes.

Lens-retinal induction cascade

An example of reciprocal and sequential inductions.

During the lens-retinal indication cascade, the optic vesicle produced different factors to induce lens placodes in competent head ectoderm. Which main factor induces?

**FGF8**

The lens placode secretes more FGFs to induce the optic vesicle to form which structure?

A) Neural retina

B) Cornea

C) Optic cup

D) Lens fiber

C) Optic cup.

The invaginated lens induces the remaining ectoderm above it to become which structure?

A) Neural retina

B) Cornea

C) Optic cup

D) Lens fiber

B) Cornea.

1\. The optic vesicle induces the head ectoderm to form the ____________.  

A) optic cup 

B) lens placode 

C) cochleovestibular ganglion 

D) pigmented retina 

E) neural retina 

B) lens placode 

The epidermis →

Skin

The skin

the largest organ in our body. It protects against dehydration, injury, and infection, and is constantly renewed via stem cells. 

What are the three major components of skin?

1. **Epidermis**
2. **Dermis**
3. Neural crest-derived **meloncytes**

What is dermis made of?

**Firoblasts**, loosely packed and derived from mesoderm

Where does the melanocytes stay?

In the basal epidermis and in hair follicles.

Mammalian epidermis starts as one layer but soon becomes a two layered structure. What does the outer layer give rise to?

**Periderm**

Periderm

Temporary covering that is shed once the inner layer differentiates to form the true epidermis.

The inner layer is also referred to as what?

**Basal layer** or **stratum germinativum**

The inner layer contains what?

Epithelial epidermal stem cells attached to a **basal lamina** (basement membrane) that the stem cells help to make.

Stem cells divide asymmetrically, producing two daughter stem cells. What are their functions?

* One stem cell remains attached to the basal lamina.
* One stem cell differentiate to a **keratinocyte**.

What signal promotes differentiation of keratinocytes?

A) Notch

B) FGF8

C) Shh

D) Pax6

E) BMP

A) **Notch**

What does induction of keratinocytes produce?

**Keratin**

Keratin

intermediate filament protein.

What does absence of Notch lead to?

Hyperproliferation of the dividing cells.