Development of the CNS

Question 1

When is the embryo particularly prone to damage by the environment

Answer 1

The 3rd trimester

Question 2

What essentially forms the CNS

Answer 2

The folding of the neural plate

Question 3

What is the initiation of neural development dependent on

Answer 3

The cells that will generate the nervous system become distinct early in the generation action of a vertebrate embryo, concurrent with the establishment of the midline and the basic body axes: anterior-posterior (mouth-anus), dorsal-ventral (back-belly), and medial-lateral (midline-periphery). These axes are foundational for proper generation of every organ in the body, including the brain. In addition, the unique curvature of the human CNS generates a distinctive rostral-caudal axis in the developing brain. The axes, and thus the initiation of neural development, are critically dependent on the process of gastrulation.

Question 4

Describe gastrulation

Answer 4

Gastrulation begins as the local invagination of a subset of cells in the very early embryo (which starts out as a single sheet of cells). By the time invagination is complete, the embryo consists of 3 layers of cells called the germ layers: an outer ectoderm, a middle mesoderm (these cells initiate the invagination that defines gastrulation); and an inner endoderm.

Question 5

What determines the midline and different axes of the embryo

Answer 5

Based on the position of the invaginating mesoderm and endoderm, gastrulation defines the midline as well as the anterior-posterior and dorsal-ventral axes of all vertebrate embryos. These axes will determine the position of all organ systems including the peripheral and CNS, as well as facial structures and appendages

Question 6

When does the development of the nervous system begin

Answer 6

At approximately 3 weeks gestation. At this point the embryo consists of 3 layers:

endoderm (forms G.I tract amongst other things)
mesoderm (forms muscles, connective tissues and blood vessels)
ectoderm (forms the entire nervous system and the skin)

Question 7

What are the walls of the neural tube lined by

Answer 7

the neuroepithelium- whose cells give rise to the CNS

Question 8

Summarise the process of early development of the nervous system

Answer 8

§ At approx. 3 weeks you get the transverse sections on the left.
§ There are 3 distinct layers – ectoderm, mesoderm and endoderm.
1. There is a proliferation of the ectoderm to form the neural plate.
2. As this thickens, the neural plate folds up on the sides and eventually fuse dorsally.
a. The space this leaves is called the neural canal.
3. A little strip of cells at the dorsal tip of the neural fold form the neural crests that run alongside the neural canal more dorsally.
a. Neural tube = all CNS cells (the wall of the neural tube is the neuroepithelium).
b. Neural crest = all PNS cells.

Question 9

Describe neurulation

Answer 9

At around day 22 of gestation, an area of ectoderm on the dorsal surface of the embryo, called the neural plate, thickens and folds to form the neural groove. The ridges on either side of the groove expand and begin to fuse in the midline approximately halfway along its length (at the level of the fourth somite). Somites are paired blocks of mesoderm segmentally arranged alongside the neural groove of the embryo. The very tips of these ridges become the neural crest, and the fused neural tube gives rise to the brain and spinal cord (CNS)

Question 10

When do the tubes at each end fuse

Answer 10

The tube at the cranial (rostral or head-end) neuropore fuses on day 25, and the caudal (tail-end) fuses on day 27.

Question 11

Summarise the neural crest cells

Answer 11

the neural crest cells give rise to most of the cells in the PNS (including the dorsal root ganglia) along with cells of the autonomic ganglia, adrenal medulla and melanocytes in the skin. Dorsal root ganglia send their developing axons into the developing spinal cord and also towards the periphery. The advancing growth cones of these neuronal processes are guided to their appropriate central and peripheral targets by means of diffusible neurotrophic factors and cell adhesion molecules.

Question 12

By the end of development, where is the segmental arrangement of the nervous system retained

Answer 12

By the end of development, the segmental arrangement of the nervous system (as determines by the somites) is retained only by the spinal cord.

Question 13

Describe the differentiation of the neuroepithelium

Answer 13

o Neuroblasts – all neurones with cell bodies in the CNS.
§ Includes upper motor neurones as cell bodies in CNS but lower MNs in PNS.
o Glioblasts – (become neuroglia) astrocytes and oligodendrocytes.
o Ependymal cells – lining ventricles and central canal.
§ Remain close to inner membrane of neural tube.

Question 14

What is a central event for the development of the nervous system

Answer 14

The formation of the notochord in the midline of the gastrulating embryo.
The notochord is a distinct cylinder of mesodermal cells that condenses at the midline as the mesoderm invaginates and extends from the mid-anterior to the posterior aspect of the embryo. It is generated at a site of a singular surface indentation called the primitive pit, which subsequently elongates to form the primitive streak. As a result of these cell movements, the notochord defines the embryonic midline and thus the axis of symmetry for the entire body

Question 15

What happens to the notochord

Answer 15

The notochord itself is a transient structure, which disappears once early development is complete. The notochord specifies the basic topography of the embryo defining the midline and axis of symmetry, determines the position of the nervous system, and is required for subsequent early neural differentiation.

Question 16

Describe the role of the notochord in neural differentiation

Answer 16

Along with cells that define the primitive pit, the notochord sends inductive signals to the overlying ectoderm that cause a subset of cells to differentiate into neuroepithelium precursor cells.

Question 17

What do the neural crest cells differentiate into

Answer 17

§ Neural crest cells – 4 types of cells differentiate from the neural crest cells:
o Sensory neurones of dorsal root ganglia and cranial ganglia.
o Postganglionic autonomic neurones.
o Schwann cells – myelinate axons in PNS.
o Non-neuronal derivatives – e.g. melanocytes- pigment cells in the skin

Question 18

Describe the proliferation of the neuroepithelium

Answer 18

§ This is a cross-section of the neural tube at an early stage.
§ There is ONE-layer of cells (it just doesn’t look it as they’re squished) and most cells are attached to both the inner and outer membrane.
§ The bigger cells towards the inside are undergoing mitosis.- inner cells show massive proliferation- lots of mitosis occurring here (seen in histology of cells)

Question 19

Summarise the migration of cells in the neuroepithelium

Answer 19

§ Once the cells have finished mitosis at the inner membrane, one daughter cell migrates to the outer.
§ At the outer, the cell develops into neuroblasts.
§ The cells develop dendrites and then axons directed away from the inner membrane.
§ Eventually you end up with 3 layers – inner membrane layer with mitosis occurring, another with neuronal soma, and another with axons.
o Defines grey (soma) and white (axons) matter.

Question 20

In what manner do the cells migrate

Answer 20

In a laminar fashion

Question 21

Where are the ventricles found

Answer 21

The ependymal layer

Question 22

Describe how the neuroblast cells of the neuroepithelium (neural tube) differentiate

Answer 22

The neural tube contains neuroblast cells. its hollow centre becomes the spinal canal. Neuroblasts adjacent to the canal divide and travel to the outer mantel layer, ultimately forming the neurons of the grey mater of the spinal cord. These neuroblasts/neurons project nerve fibres that grow outwards into the marginal zone, ultimately forming the white mater of the spinal cord.

Question 23

Summarise the differentiation of the glioblasts and ependymal cells

Answer 23

Glioblasts show a similar pattern of differentiation but can migrate to the white (axon) matter as well (Glioblasts do NOT develop axons, but do develop processes). Ependymal cells just remain in the ependymal layer.

Question 24

Describe some of the mediators involved in the differentiation of the neuroepithelium

Answer 24

The cells at the ventral midline of the neural tube differentiate into a specialised strip of epithelial-like cells called the floorplate (reflecting their position at the ventral and medial part of the neural tube- above the notochord). Molecular signals from the floorplate as well as from the notochord specify position and fate for the neuroectodermal precursors of the spinal cord and hindbrain.

Question 25

Where do the signals to differentiate come from in the forebrain

Answer 25

In the forebrain, non-floorplate ventral midline structures s well as neural-crest derived mesenchyme immediately adjacent to the prosencephalic vesicle provide similar signals.

Question 26

As well as cell type what else do the neuroectodermal precursor cells determine

Answer 26

Eventually, subsets of the neuroectodermal precursor cells generate region- and fate-specified neural progenitors that differentiate into specific classes of neurons in distinct brain structures.

Question 27

Describe how the neuroectodermal cells determine the migration of the cells

Answer 27

Signals from the floorplate, the somites, and the cranial neural crest for the forebrain lead to differentiation of cells in the ventral neural tube that eventually give rise to spinal and hindbrain motor neurones, closest to the ventral midline, or basal forebrain structures as well as related interneurons, once again closest to the ventral midline.
Precursor cells further away from the ventral midline give rise to sensory realy neurons and related interneurons in more dorsal regions of the spinal cord and hindbrain.

Question 28

What is the differentiation of the dorsal cell groups facilitated by

Answer 28

A narrow strip of neuroepithelial cells at the dorsal midline of the neural tube referred to as the roofplate of the spinal cord.
Like the notochord, the floorplate and roofplate are transient structures that provide signals to the developing neural tube and all but disappear once initial nervous system development is complete

Question 29

Summarise the layers and differentiation of the neural tube

Answer 29

§ There are 3 clear layers:
o Inner – Ependymal layer – germinal layer.
o Middle – Grey matter – mantle layer.
o Outer – White matter – marginal layer.
§ The process of differentiation is controlled by signalling molecules secreted from surrounding tissues that bind with receptors on neuroblasts.
§ These control migration and axonal growth by attraction and repulsion.
§ Differentiation then depends upon concentration gradient and timing.
o Concentration gradient – close to source of molecules = higher conc.
o Timing – only produce s. molecules when developing neurones have the correct receptors to receive them.

Question 30

What ultimately controls differentiation

Answer 30

Selective signalling molecules- which determine how far and where the cells migrate to in their development- as well as what they develop into.
Trophic and inhibitory signals present

Question 31

Describe the sonic hedgehog

Answer 31

Peptide hormone essential for induction in the developing nervous system. Particularly important for 2 phases:
closing the neural tube, especially the anterior midline, and establishing the identity of neurones- in the ventral portion of the spinal cord and hindbrain.
The transduction of signals via the sonic hedgehog requires the cooperation of two surface receptor proteins, patched and smoothened.

Question 32

How does the arrangement of white and grey mater differ in the brain and spinal cord

Answer 32

Spinal cord- white mater is the marginal layer

Opposite in the brain

Question 33

Summarise the developing spinal cord

Answer 33

Cross-section through neural tube later on in development. Two significant features:
§ Neural canal is much smaller than thickness of wall.
§ Grey matter is split into two distinct types:
o Alar plate – dorsal.
§ Receive sensory information.
o Basal plate – ventral.
§ Has some inter-neurones but also motoneurons to send information out of the ventral roots.

Question 34

Describe the two populations formed by the neuroblasts in the primitive grey mater

Answer 34

Dorsal alar plate and a ventral basal plate separated by a shallow groove (sulcus limitans):
the alar plate forms the sensory cells and interneurons of the dorsal horn
the basal plate cells form the motor cells of the ventral horn along with sympathetic (thoracic) and parasympathetic (lumbar and sacral regions) preganglionic neurons

Question 35

Summarise the control of differentiation

Answer 35

Control of differentiation: signalling molecules secreted by surrounding tissue interact with neuroblast receptors to control migration and axonal growth - depending on concentration gradient and timing (attraction and repulsion)

Question 36

What does the mesenchymal tissue around the neural tube form

Answer 36

The mesenchymal tissue around the neural tube forms the coverings of the brain and spinal cord.

Question 37

Compare the length of the spinal cord to the vertebral column throughout development

Answer 37

In the first 8 weeks of gestation, the spinal cord is the same length as the vertebral column. After 8 weeks the vertebral column grows at a faster rate. By 40 weeks of gestation (term), the spinal cord stops at the level of L3 and, in adults, it ends at L1. The spinal nerve roots below this level descend within the vertebral canal until they reach the appropriate exit foramen. The pia mater remains attached to the coccyx and, therefore, elongates with respect to the spinal cord. The strand of pia mater between the coccyx and the lower end of the spinal cord is known as the filum terminale, and collectively with the individual nerve roots below L1, as the cauda equina (literally ‘horse’s tail’).

Question 38

Describe cauda esquina syndrome

Answer 38

A prolapsed intervertebral disc or fracture can cause compression of the cauda equina. The symptoms of this include pain in the nerve distribution of the root affected, saddle anaesthesia (around the anus) and disturbance of bladder/bowel function. It is a neurosurgical emergency and the pressure must be relieved to preserve the function of the nerves.

Question 39

Which types of neurons do the alar plate and basal plate give rise to?

Answer 39

Alar plates- interneurons (receive sensory information)

Basal plates- motor neurones and interneurones

Question 40

Describe the cell types that the neural crest cells give rise to

Answer 40

The neural crest cells give rise to most of the cells in the peripheral nervous system (including the dorsal root ganglia) along with cells of the autonomic ganglia, adrenal medulla and melanocytes in the skin. Dorsal root ganglia send their developing axons into the developing spinal cord and also towards the periphery. The advancing growth cones of these neuronal processes are guided to their appropriate central and peripheral targets by means of diffusible neurotrophic factors and cell adhesion molecules.

Question 41

By the end of development, where is the segmental arrangement of the nervous system retained

Answer 41

As determined by the somites

In the spinal cord

Question 42

Summarise the spinal reflex

Answer 42

Sensory info in via DRG

Single synapse to motor neuron in ventral horn- out to musculature

Question 43

Describe the purpose of the interneurones

Answer 43

Sensory info from DRG- into interneurones in different pathways depending on the sensory modality (i.e pain and temp take a different pathway to touch and proprioception)

Question 44

Summarise the mature spinal cord

Answer 44

Butterfly arrangement of grey mater
§ The neural canal à central canal and now carries CSF.

§ Alar plate develops à the dorsal horns.

§ Basal plate develops à the ventral horns.

§ Whole spinal cord becomes surrounded by a thick layer of white matter.

Neural canal is surrounded by ependymal cells
Central canal also shrinks

Question 45

Describe dorso-ventral patterning

Answer 45

 The notochord is found just below the basal plate (ventral side).
 The notochord produces several signalling molecules and a concentration gradient is established with the highest concentration near the notochord.
o The cells within the neural tube closest to the notochord therefore are induced to become motor neurones (in basal plates).
 The ectoderm (dorsal to neural tube) also produces signalling molecules and these also establish a concentration gradient but these tend to inhibit cell differentiation into motor neurones.

Question 46

Summarise the development of the brainstem

Answer 46

The brainstem has the same basic structure as the spinal cord, except that it has to accommodate the large motor and sensory tracts that run between the spinal cord and the brain.

Question 47

Describe the development of the medulla of the brainstem

Answer 47

Initially, the myelencephalon or medulla is organized like the primitive spinal cord with alar and basal plates. As it flattens out further up, forming the floor of the fourth ventricle, the alar plates (sensory cell groups) move outwards until they lie lateral to the basal plates (motor cell groups). Other cells from the alar plate migrate ventrolaterally to form the olivary nuclei.
Neural tube not closed here

Question 48

What are the basal plates medial and alar plates lateral in the brainstem

Answer 48

early development occurs in a tubular fashion, similar to spinal cord, and lateral proliferation of the roof plate enlarges the canal to form the 4th ventricle - this causes the basal plate to lie medially and the alar plates laterally, dictating the pattern of cranial nerve nuclei

Question 49

How are the cells of the alar and basal plates in the brainstem arranged

Answer 49

The cells of the alar and basal plates are arranged in columns according to whether they innervate somatic (body wall) or visceral (internal organ) structures:
•
The basal plate forms the motor nuclei for cranial nerves IX, X, XI, XII.
•
The alar plate forms sensory nuclei for cranial nerves V, VIII, IX, X along with the gracile and cuneate nuclei (receiving inputs from the spinal cord).

Question 50

Describe the development of the pons

Answer 50

The pons is formed by the anterior part of the metencephalon and part of the alar plate of the medulla. It contains a thick band of fibres (important in motor processing) which connect the forebrain with the cerebellum. The neurons of the ventromedial alar plate at this level form:
•
The main sensory nucleus of V
•
A sensory nucleus of VII
•
Vestibular and cochlear nuclei of VIII
•
Pontine nuclei.
The neurons of the basal plate form the motor nuclei of V, VI and VII.

Question 51

Describe the development of the cerebellum

Answer 51

The cerebellum develops from the most posterior parts of the alar plates, above the level of the medulla. Cerebellar growths project over the top of the fourth ventricle and fuse in the midline, with migrating cells from the alar plates becoming the cerebellar cortex.