Lecture 7 - Chapter 22: Early brain development Flashcards
Describe the early stages of embryonic development (embryogenesis).
Zygote → cell divisions into morula → cell divisions into blastula → gastrulation and the arise of three layers: mesoderm, endoderm and ectoderm.
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.
- Mesoderm → skeletal, muscular and cardiovascular systems
- Endoderm → urinary, digestive and respiratory systems
- Ectoderm → skin and nervous system
What is the process of neurulation?
- 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.
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 ….
- 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.
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.
- Sensory ganglia
- Autonomic ganglia
- Adrenal chromaffin cells
- Melanocytes
Study picture closely
Ok
Sometimes the process of neurulation goes wrong. Name three neural tube defects.
- 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.
Where is neuronal patterning dependent on?
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.
Name examples of morphogens and examples of transcription factors that are activated by morphogens.
- 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.
Just study?
What are teratogens?
Agents that cause malformations in embryos
Why do inductive signals like RA act as teratogens?
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).
What are most expression patterns that induce e.g. dorsoventral or anteroposterior specification based on?
They’re based on a concentration gradient induced by inductive signals (morphogens).
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?
- 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.
Describe dorsoventral specification/patterning.
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.
What is anteroposterior specification?
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.
Describe anteroposterior specification.
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.
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.
- Prosomeres → prosencephalon
- Midbrain segments → mesencephalon
- Rhombomeres → rhombecephalon
From the prosencephalon, mesencephalon and rhombecephalon structures, more specific brain structures are able to develop. What are these?
- 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).
Explain briefly how neuroepithelial cells become dopaminergic neurons in the substantia nigra/VTA of the midbrain (mesencephalon).
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).
Radial specification is really challenging for neurons. How do neurons migrate to the outer rim of i.e. the cortex?
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.
Explain how radial patterning/specification occurs.
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.
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.
- 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
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.
- 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
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.
- 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
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.
- 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.
Study this picture as it supports the previous questions.
Name three pleiotropic effects of the Shh gene and also name defects that result from the lack (or abundance) of this gene.
- Important in early brain development, without Shh the midline of the brain doesn’t develop.
- 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.
- Shh also has function in adult life. It is known that basal cell carcinoma are dependent on Shh signaling.
