Lecture 7 - Chapter 22: Early brain development

Question 1

Describe the early stages of embryonic development (embryogenesis).

Answer 1

Zygote → cell divisions into morula → cell divisions into blastula → gastrulation and the arise of three layers: mesoderm, endoderm and ectoderm.

Question 2

A gastrula contains three different layers: mesoderm, endoderm and ectoderm. Differentiation of cells that originate from one of these layers, results in the arisal of tissue-specific cells. Describe what tissues arise from the three layers.

Answer 2

• Mesoderm → skeletal, muscular and cardiovascular systems
• Endoderm → urinary, digestive and respiratory systems
• Ectoderm → skin and nervous system

Question 3

What is the process of neurulation?

Answer 3

• Here, the neuroectodermal tissues differentiate from the ectoderm and thickens into the neural plate.
• The neural plate bends dorsally and the two ends eventually join at the neural plate borders (now called the neural crest). This is called invagination.
• The neural tube closes, which causes the neural crest cells to disconnect from the epidermis. The neural crest cells migrate and become part of the peripheral nervous systems.

Question 4

Fill in:

• The neural tube is the embryonic form of the ….
• The notochord is the embryonic form of the ….
• The neural crest is the embryonic form of the ….

Answer 4

• The neural tube is the embryonic form of the central nervous system (brain and spinal cord).
• The notochord is the embryonic form of the vertebral column.
• The neural crest is the embryonic form of the peripheral nervous system.

Question 5

The neural crest cells migrate and become part of the peripheral nervous systems. They migrate to four different places to differentiate into certain tissues. Name the four tissues that neural crest cells migrate to and differentiate in.

Answer 5

1. Sensory ganglia
2. Autonomic ganglia
3. Adrenal chromaffin cells
4. Melanocytes

Question 6

Study picture closely

Answer 6

Ok

Question 7

Sometimes the process of neurulation goes wrong. Name three neural tube defects.

Answer 7

• Spina bifida (split spine in latin), incomplete closing of the spine and the membranes around the spinal cord.
• Anencephaly , failure closing rostral (head) end of the neural tube.
• Exencephaly, early stage of anencephaly wherein the brain is located outside the skull.

Question 8

Where is neuronal patterning dependent on?

Answer 8

On extrinsic inductive signals, called morphogens. Morphogens are produced by surrounding cells that can induce differentiation in the neuronal tube, by changing intrinsic gene expression by inducing expression of transcription factors.

Question 9

Name examples of morphogens and examples of transcription factors that are activated by morphogens.

Answer 9

• Morphogens → chordin, noggin, bone morphogenic proteins (BMPs), Wnt, FGF, retinoic acid (RA), Sonic Hedgehog (Shh), etc.
• Transcription factors → Hox, Pax, Msx, Olig, Sox, Snail, bHLH, etc.

Question 10

Just study?

Question 11

What are teratogens?

Answer 11

Agents that cause malformations in embryos

Question 12

Why do inductive signals like RA act as teratogens?

Answer 12

Small amounts of maternally supplied RA activate too much gene expression in the embryonic forebrain and results in serious brain malformations.

(On the picture A and B, the right picture is the normal development and the left picture is embryos from mothers treated with RA (RA induced gene expression is indicated in blue).

Question 13

What are most expression patterns that induce e.g. dorsoventral or anteroposterior specification based on?

Answer 13

They’re based on a concentration gradient induced by inductive signals (morphogens).

Question 14

In regard to dorsoventral specification:

• Where is chordin highest expressed and what does it induce?
• Where is noggin hihest expressed and what does it induce?

Answer 14

• Chordin is derived from the notochord and induces motor neuron differentiation on the ventral side. Therefore chordin is highest in concentration around the notochord and lowest far away from the notochord.
• On the dorsal side, noggin is highly expressed. This induces sensory neuron differentiation dorsally.

Question 15

Describe dorsoventral specification/patterning.

Answer 15

The neural tube will eventually differentiate into the spinal cord, where the spinal cord ventrally contains motor ganglia and dorsally contains sensory ganglia.

Dorsoventral specification is based on inductive signals (morphogens) that act together, where certain transcription factors are only expressed dorsally or ventrally.

• Chordin is derived from the notochord and induces motor neuron differentiation on the ventral side. Therefore chordin is highest in concentration around the notochord and lowest far away from the notochord.
• On the dorsal side, noggin is highly expressed. This induces sensory neuron differentiation dorsally.

Question 16

What is anteroposterior specification?

Answer 16

It is the differentiation and specification of the head (rostral) and the tail (caudal) via specfic transcription patterns. It is important so that the brain develops anteriorly and the spinal cord caudally. It requires specific expression patterns of HOX genes.

Question 17

Describe anteroposterior specification.

Answer 17

Different HOX genes are combined in clusters. The combination of these specific HOX genes in clusters at each location determines how the neural tube develops. This is called colinear expression of HOX genes. This colinear expression is regulated by retinoic acid (RA) that is produced by Hensen’s node.

Concentrations of RA are thus highest around Hensen’s node. Due to embryonic development, as the embryo grows, Hensen’s node moves from its anterior location to a more posterior location. Therefore RA concentrations become higher towards the caudal/tail and become lower towards the rostral/head.

Question 18

The brain also develops through a tube-like structure, composed of six forebrain segments (prosomeres), one midbrain segment and eight hindbrain segments (rhombomeres). These segments then built up three main brain structures, that are seen as the enlargements of the neural tube. Name these three main brain structures.

Answer 18

• Prosomeres → prosencephalon
• Midbrain segments → mesencephalon
• Rhombomeres → rhombecephalon

Question 19

From the prosencephalon, mesencephalon and rhombecephalon structures, more specific brain structures are able to develop. What are these?

Answer 19

• Myelencephalon → medulla oblongata (lower part of brainstem)
• Metencephalon → middle part of the brainstem
• Mesencephalon → upper part of the brainstem
• Diencephalon → thalamus and optic lobes
• Telencephalon → cortex.

For the dutchies → ezelsbruggetje om volgorde van buitenste hersenstructuur naar binnenste hersenstructuur te onthouden → tel die mes met my → Tel(encephalon), die(ncephalon), mes(encephalon), met(encephalon), my(elencephalon).

Question 20

What are characteristics of (neural) stem cells?

Answer 20

• Multipotent (can become anything)
• Unlimited capacity to divide
• Self-renewing

Question 21

Where in the brain do neural stem cells reside during embryonic development and where in the brain do neural stem cells reside during adulthood?

Answer 21

• In the ventricular zone lie neuroepithelial stem cells that can generate any kind of neurons and are only active during embryonic development.
• In the subventricular zone lie germinal stem cells that can only generate new interneurons.

Question 22

What neurons can’t be regenerated after embryonic development and what neurons can still be generated during adulthood?

Answer 22

• Motorneurons are only generated during embryonic development and thus originate from the neuroepithelial stem cells in the ventricular zone.
• Interneurons can be generated during adulthood and thus originate from the germinal zone in the subventricular zone.

Question 23

Where do these interneurons that are generated in the germinal zone of the subventricular zone migrate to?

Answer 23

Interneurons migrate to the olfactory bulb (smell) and to the hippocampus.

This makes sense, since neurons important for smell quickly die when exposed to certain smells. So regeneration is needed. New neurons in the hippocampus are needed to learn and form new memories.

Question 24

What is needed before stem cells become a specific type of neuron?

Answer 24

Cell migration to the right location

Question 25

Explain briefly how neuroepithelial cells become dopaminergic neurons in the substantia nigra/VTA of the midbrain (mesencephalon).

Answer 25

Neuroepithelial cells from the ventricular zone migrate to the midbrain by the sequential action of transcription factors/inductive signals until they reach their final position. Once fully matured, they then express the marker tyrosine hydroxylase (enzyme needed to produce dopamine).

Question 26

What might be a solution to Parkinson's disease?

Answer 26

Reprogramming stem cells to become DA neurons and restore the function of substantia nigra.

Question 27

Radial specification is really challenging for neurons. How do neurons migrate to the outer rim of i.e. the cortex?

Answer 27

They make use of radial glial cells that have their cell bodies in the ventricular zone and have extensions all the way to the cortex. These extensions form a guide for neurons to travel up to their final location.

Question 28

Explain how radial patterning/specification occurs.

Answer 28

This process is important for the layering of the cortex. When the brain has fully developed, there should be 6 layers that have different characteristics (i.e. different types of neurons). The first neurons that are “born” in the ventricular zone are deposited in the lowest (sixth) layer and in the next step neurons travel _through_ the sixth layer to form the fifth layer.

Question 29

There are all kinds of defects in migration (cortical migration defects). What is an initiation defect? Also explain what genes cause this defect and what disorder it causes.

Answer 29

* The initiation effect is where neurons are generated in the ventricular zone, but some of these neurons stay in the ventricular zone. * This results in microcephaly (small brain) * Genes that cause this defect are filamin and Arfgef2

Question 30

There are all kinds of defects in migration (cortical migration defects). What is an ongoing migration defect? Also explain what genes cause this defect and what disorder it causes.

Answer 30

* The ongoing migration defect is where generated neurons in the ventricular zone **do** migrate towards the cortical layer, but this process is random and numerous. This results in no specification of the layers. * It causes lissencephaly (loss of cortical layering) and a double cortex. * Genes that cause this defect are Dcx and Lis1

Question 31

There are all kinds of defects in migration (cortical migration defects). What is an lamination defect? Also explain what genes cause this defect and what disorder it causes.

Answer 31

* The lamination defect is where the first neurons that are generated are deposited in the sixth initial layer, but where the next set of ‘incoming’ neurons push the first set of neurons upwards to the next layer, instead of going through this layer. * This causes inverted cortical layering. * Genes that cause this defect are reelin and Apoer2

Question 32

There are all kinds of defects in migration (cortical migration defects). What is a stop signal defect? Also explain what genes cause this defect and what disorder it causes.

Answer 32

* After layering of the cortex is complete, neurons should receive a signal to stop migration to the cortical layers. In this defect, this stop signal is absent. This causes the neurons to migrate outside the meningeus. * It causes Walker-Warburg syndrome, also referred to as Cobblestone complex. * Genes that cause this defect are Fak and POMT1.

Question 33

Study this picture as it supports the previous questions.

Question 34

What is pleiotropism?

Answer 34

The control by a single gene of several distinct and seemingly unrelated phenotypic effects.

Question 35

Name a gene that is important during embryonic development that has pleiotropism.

Answer 35

Shh gene, important in early brain development.

Question 36

Name three pleiotropic effects of the Shh gene and also name defects that result from the lack (or abundance) of this gene.

Answer 36

1. Important in early brain development, without Shh the midline of the brain doesn't develop. 2. Shh is also important in cell migration in the cerebellum. Here Purkinje cells secrete Shh, where Shh acts as a morphogen that causes granular neurons to migrate towards the inner part of the cerebellum. This causes the inner part of the cerebellum to grow. It occurs after birth and is disturbed in children with medulloblastoma due to this process. 3. Shh also has function in adult life. It is known that basal cell carcinoma are dependent on Shh signaling.

Question 37

What can you conclude based on the fact that Shh is important in brain development but also occurs in basal cell carcinoma (skin cancer)?

Answer 37

Skin and nervous system both originate from the ectoderm, which is probably the reason why certain functions/genes (like Shh) are conserved in both organs.