Case 1 Flashcards
when and what is gastrulation?
- third week of development
- phase early in the embryonic development, during which the single-layered blastula is reorganised into a bilaminar disc and then further into a trigeminal (‘three-layered’) structure known as the gastrula
- these three germ layers are known as the ectoderm, mesoderm and endoderm
describe the process of gastrulation
The epiblast and hypoblast layers are still connected. There is a point where the cells in these two layers are held tightly together, causing it to be slightly thicker than the rest of the ‘epiblast plate’. This is called the prechordal plate (this will form the mouth of the baby). This is important as it shows us which side of the epiblast plate will be the cephalic (head) end and which will be the caudal (tail) end.
Gastrulation begins with the formation of the primitive streak and primitive node. This is a longitudinal depression of cells at the caudal end of the epiblast plate (primitive streak) with a dilation of depression (primitive node) towards the middle of the epiblast plate.
The cells of the epiblast begin to proliferate and migrate towards the primitive streak (due to the depression).
These cells will continue to migrate towards the primitive streak and eventually pass under the primitive streak and form a layer between the epiblast and hypoblast layers.
This begins to form the trigeminal disc: ectoderm, mesoderm and endoderm.
The cells that pass under the primitive ‘node’ will migrate towards the prechordal plate. This collection of cells is called the notochord.
Above the notochord is the ectoderm; below it is the endoderm and to its sides is the mesoderm.
The ectoderm that lies immediately above the notochord, called the neuroectoderm, gives rise to the entire nervous system.
when and what is neurulation?
day 22
Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula.
folding and closure of the neural plate
describe neurulation
The notochord sends inductive signals to the overlying ectoderm, causing the central part of the ectoderm to proliferate and form a longitudinal thickening from the primitive node to the prechordal plate.
The cells of this thickening are called neuroectodermal cells.
These differentiate into a distinct columnar epithelium called the neural plate.
The medial margin of the neural plate begins to depress downwards to form the neural groove.
The lateral margin of the neural plate becomes elevated. This is called the neural fold.
Eventually, the neural fold will keep on elevating, until they fuse. This fusion will continue cephalically and caudally, forming the neural tube.
The opening of the neural tube at the cephalic end is called the anterior neuropore and the opening of the neural tube at the caudal end is called the posterior neuropore.
The anterior neuropore closes at the 25th day of gestation and the posterior neuropore closes on the 27th day of gestation.
o This time of pregnancy is crucial because this is the time where the pregnant lady will miss her period due to the pregnancy. Also, this is the time where pregnant ladies are told to have ample folic acid
o If there is a deficiency in the levels of folic acid, then the anterior and posterior neuropores will not close properly.
o Failure of closure of the anterior neuropore is called Anencephaly – the brainstem forms, but the upper part of the brain doesn’t develop - the baby is not compatible with extra-uterine survival.
o Failure of closure of the posterior neuropore is called Spina Bifida.
Once the neural folds have fused to form the neural tube, cells from the neural fold region, called neural crest cells, begin to migrate underneath the ectoderm + into the surrounding mesoderm and the endoderm too.
Somites grow alongside the neural tube in pairs. Somites develop in succession, starting from the cranial end and finishing at the caudal end. A new pair of somites develops every 90 minutes and there are 44 pairs in total. These will form skeletal muscles, the vertebrae, the ribs, the dermis, cartilage and tendons.
the remnant of the notochord in adults is presented by what?
the nucleus pulposus (within the fibrous annulus ring) in the intervertebral disc
what are derivatives of the neural tube?
- vesicles
- alar and basal plates
- tracts
- pons
describe the formation and development of vesicles
Once the anterior neuropore has closed, the cephalic (head) end of the neural tube begins to form three swellings bilaterally, called primary vesicles.
The 3 primary vesicles are (starting from superior to inferior):
1. Prosencephalon (forebrain)
2. Mesencephalon (midbrain)
3. Rhombencephalon (hindbrain)
Two flexures are formed:
1) The cervical flexure at the junction between the hindbrain and the spinal cord.
2) The cephalic/pontine flexure which is the first bend of the embryonic brain, in the mesencephalon region.
These 3 primary vesicles then develop into 5 secondary vesicles:
o The Prosencephalon gives rise to the following secondary vesicles:
1. Telencephalon – rapidly growing. Dorsal territory gives rise to the cerebrum and hippocampus, whilst the ventral territory gives rise to the basal ganglia, basal forebrain nuclei and olfactory bulb. In short, it forms the four lobes of the brain: frontal lobe, parietal lobe, occipital lobe and temporal lobe.
2. Diencephalon – slow growing. This forms the thalamus, hypothalamus, epithalamus, subthalamus, uvea (choroid, iris, ciliary body) and the retina.
o The Mesencephalon doesn’t develop into secondary vesicles:
3. Mesencephalon (Midbrain)
o The Rhombencephalon gives rise to the following secondary vesicles:
4. Metencephalon – posterior aspect of this develops into the cerebellum, whilst the anterior aspect forms the pons.
5. Myelencephalon – this forms the medulla oblongata.
The pontine flexure forms the boundary between the metencephalon and the myelencephalon.
what is segmentation? what controls it?
The process of segmentation establishes regional identity in the body of the developing embryo by dividing it into repeating units. This is controlled by Hox genes. In some cases their pattern of expression coincides with, or even precedes, the formation of morphological features such as the various bends, folds, and constrictions that signify the progressive regionalisation of the developing neural tube. Hox gene expression does not extend into the midbrain or forebrain.
describe the formation and development of alar and basal plates
The wall of a recently closed neural tube consists of neuroepithelial cells. Once the tube closes, neuroepithelial cells begin to give rise to neuroblasts. They form the mantle layer, a zone around the neuroepithelial layer. The mantle layer later forms the gray matter of the spinal cord. Grey matter is the collection of cell bodies.
At the caudal end of the neural tube the neuroblasts proliferate outwards:
o Postero-laterally to form the Alar Plates (sensory grey matter). These are also known as the Dorsal Horns.
(Alar are ears and they are concerned with senses, hence sensory grey matter)
o Antero-laterally to form the Basal Plates (motor grey matter). These are also known as the Ventral Horns.
The sulcus lamitans, present on the inner lateral walls of the neural tube, separates the neural tube in a ventral area (basal plates) and a dorsal area (alar plates).
The cell bodies (neuroblasts) in the outer region of the basal plates develop nerve fibres (processes) that extend out to the peripheries, forming the motor nerves. These are called motor roots.
At the same time, some of the neural crest cells that migrated outwards to the peripheries will proliferate to form the dorsal root ganglions. The cell bodies in these ganglions will develop nerve fibres that will extend to the peripheries AND nerve fibres that will extend to the cell bodies in the outer region of the alar plates. The nerve fibres (processes) between the alar plate and the dorsal root ganglion are called the sensory root.
The outermost layer of the spinal cord, the marginal layer, contains nerve fibres emerging from neuroblasts in the mantle layer. As a result of myelination of nerve fibres, this layer is called the white matter of the spinal cord.
describe the development of the tracts and other aspects of the spinal cord
Some cell bodies in the centre of the alar and basal plates, form nerve fibres which extend upwards (on the posterior side of the spinal cord), forming the ascending tracts. These nerve fibres collectively form the dorsal column.
Some cell bodies in the centre of the alar and basal plates, form nerve fibres which extend to the opposite alar plate and then extend upwards (on the lateral side of the spinal cord), forming the lateral (ascending) tracts. These nerve fibres collectively form the lateral column.
Some cell bodies in the centre of the alar and basal plates, form nerve fibres which extend anteriorly, crossing the nerve fibres from the opposite alar plate and then extending upwards (on the anterior side of the spinal cord), forming the anterior (ascending) tracts. These nerve fibres collectively form the ventral column.
The nerve fibres entering the dorsal root from the dorsal root ganglion will follow the course of the anterior (ascending) tracts and the lateral (ascending) tracts, and will form part of the ventral column and lateral column respectively.
At the same time, cells of white matter begin to dissolve at the anterior aspect of the spinal cord, forming the anterior median fissure.
Similarly, some cells of the white matter on the posterior aspect of the spinal cord dissolves, forming the posterior median sulcus.
describe the development of the pons - which region of pons is motor and which sensory
At the anterior aspect of the metencephalon, the pons will develop.
Here, the neural tube is arranged as such that the if you imagine someone has stuck their hand in the posterior median sulcus and pushed laterally and round so that the two anterior motor horns (basal plates) are pushed together at the point of the anterior median fissure, and lateral to them are the dorsal horns (alar plates), which have been pushed all the way round to the anterior aspect.
This means that the centre of the pons is the motor region, whilst the lateral part is the sensory region.
describe the development of derivatives of neural crest cells
- Initially, when the neural crest cells begin to spread, after the fusion of the neural fold, they spread out underneath the ectoderm. This gives rise to cells in the skin - Melanocytes
- Some of the neural crest cells are plastered around the entire neural tube and the derivative structures. This means that the neural crest cells surround the entire central nervous, including the entire brain and the spinal cord. This gives rise to the Arachnoid Mater and Pia Mater (Leptomeninges).
- Some of the neural crest cells made aggregates throughout the length of the nervous system. These are the Sensory + Autonomic Ganglia of the Cranial Nerves and the Peripheral Spinal Nerves.
- Schwann cells – myelination of the peripheral nervous system.
- Some neural crest cells combine with the mesoderm to form the some Bones of the Neurocranium.
- Sympathetic ganglia combine to form ‘glands’ that have lost their axons so they don’t innervate directly to the tissue, but instead secrete their neurotransmitters directly into the blood. This is the Adrenal Medulla, and is a neural crest cell derivative.
- Calcitonin producing para-follicular cells of the thyroid gland.
- Odentoblasts (in the teeth) that provide us with dentin in the early stages of our lives.
describe and explain neuronal migration in the PNS
• The neural crest arises from the dorsal neural tube along the entire length of the spinal cord and hindbrain.
• Thus, as neural crest cells begin to migrate, they carry with them information about their point of origin, including expression of distinct Hox genes that are limited to various spinal cord and hindbrain domains.
• Regardless of where neural crest cells originate, all of these cells must undergo an essential transition in order to begin their migration.
They all begin as neuroepithelial cells, and thus have all of the cellular junctions and adhesive interaction that keep epithelial cells in place.
To move, neural crest cells must downregulate expression of these adhesive genes and undergo an epithelial-to-mesenchymal transition.
Thus, presumptive neural crest cells express several transcription factors, including the bHLH family members Snail1 and Snail2, which repress expression of intercellular junctional proteins and epithelial adhesion molecules.
When the now motile neural crest cells reach their final destination, they cease to express Snail1/Snail2 and other transcription factors that favour the mesenchymal, migratory state.
This change is thought to reflect the integration of a number of signals that neural crest cells encounter along their migratory route.
• Neural crest cells are largely guided along distinct migratory pathways provided by non-neural peripheral structures like somites.
what guides neuronal migration in the CNS?
The mechanisms of neuronal migration are diverse, and the successful completion of migration is essential for many aspects of normal brain function.
A minority of nerve and glial cells in the CNS use existing axon pathways as migratory guides.
During development, newborn neurons (neuroblasts) use the long processes of radial glia as scaffolds, traveling along the radial glial fibers in order to reach their final destinations.
the nervous system is patterned along which axes?
anteroposterior and dorsoventral axes
what is essential for the patterning of the DV and AP axes?
secreted molecules called morphogens
what is each axis set up by?
- DV axis is set up by TGF-β family of proteins and SHH (sonic hedgehog).
- AP axis is set up by retinoic acid and FGF and homeotic genes.
what do dorsal (sensory) and ventral (motor) regions of the developing spinal cord depend upon? (DV axis)
concentration gradients between members of the transforming growth factor beta (TGF-β) family of growth factors secreted in the dorsal neural tube and sonic hedgehog (SHH) secreted by the notochord and floor plate
describe how the two concentration gradients are formed in the DV axis
• Initially bone morphogenetic protein (BMP) 4 & 7 are secreted by the ectoderm overlying the neural tube, and the presence of these proteins establishes a second signaling centre in the roof plate.
• Then, BMP4 in the roof plate induces a cascade of TGF-β proteins, including BMP5, BMP7, activin, and dorsalin in the roof plate and surrounding area.
This cascade is organized in time and space such that a concentration gradient of these factors is established (see image – there is diminishing concentration of BMP4, 7 and 5, dorsalin and actin from the dorsal to ventral region of the neural tube).
• As a result, cells near the roof plate are exposed to the highest concentrations with more ventrally positioned cells seeing less and less of these factors.
This is why the TGF-β is secreted (mainly) into the dorsal neural tube.
(Bear in mind that the roof plate side of the neural tube (longitudinally) is at the posterior (dorsal) side of the spinal cord).
- Similar events occur in the ventral region of the neural tube, only the signaling molecule is sonic hedgehog (SHH).
- During neural tube development, Shh binds to a receptor encoded by the PTCH1 gene.
- This factor is first expressed in the notochord followed by the establishment of a second signaling center in the floor plate.
- As a result, there is diminishing concentration of SHH from the ventral to the dorsal region of the neural tube.
thus, what is formed in the DV axis? what does this activate?
Thus, two overlapping concentrations are established between the TGF- β family members and SHH.
These gradients then activate transcription factors that regulate differentiation of sensory and motor neurons.
what are the BMP receptors?
- BMP receptors are serine/threonine kinases that phosphorylate a group of cytoplasmic proteins called SMADS (SMAD4 and R-SMAD).
- Upon phosphorylation, SMAD multimers translocate to the nucleus and interact with other DNA-binding proteins, thus modulating gene expression in response to the BMP signal.
describe how the anterior-posterior axis is formed
- AP axis is set up by retinoic acid and FGF and homeotic genes.
- FGF is secreted into the posterior axis of the neural tube (caudal end).
- Retinoic acid is secreted into the anterior axis of the neural tube (cephalic end).
- The gradient is formed in this axis too.
- Diffusible molecules are essential for the setting up of the AP axis (extrinsic clues)
- FGF (fibroblast growth factor) – family of molecules
- number of FGFs expressed by embryo at different stages
- FGF 4 and 8 are important – expressed in gradient
- somites form a gradient of retinoic acid (RA)
• Homeotic genes also play a role in the establishment of the AP axis (intrinsic clues).
the initial differentiation of neurones and glia
- where are precursor cells located
- how are new stem cells formed
- how are neuroblasts generated
- what are transit amplifying cells
- what happens as cells become post-mitotic
- The precursor cells are located in the ventricular zone, the innermost cell layer surrounding the lumen of the neural tube.
- New stem cells are from symmetrical divisions of neuroectodermal cells. These cells divide relatively slowly and can renew themselves indefinitely.
- In contrast, neuroblasts are generated from cells that divide asymmetrically - one of the two daughters becomes a post-mitotic neuroblasts while the other re-enters the cell cycle to give rise to another post-mitotic progeny via an asymmetric division.
- These asymmetrically dividing progenitors divide more rapidly, have a limited capacity for division overtime, and are molecularly distinct from the slowly dividing precursors.
- These cells are also known as transit amplifying cells.
• As cells become post-mitotic, they leave the ventricular zone and migrate to their final positions in the developing brain.
• In most regions of the brain where neurons are arranged into layered structures there is a systematic relationship between the layers and the time of cell origin.
Thus, each layer consists of a cohort of cells generated during a specific developmental period.
The implication of this phenomenon is that common periods of neurogenesis are important for the development of the cell types and connections that characterize each layer.
when does the anterior neuropore close?
at the 25th day of gestation
when does the posterior neuropore close?
at the 27th day of gestation
all neural tube defects are aetiologically related - what does this mean for risk of relatives developing NTD?
All neural tube defects are aetiologically related (related in terms of the causation of the defect), therefore, if one person in a family is affected, then there is an increased risk in relatives for all types of neural tube defects.
what is dysraphism?
“Dysraphism” is used when there is continuity between the posterior neuroectoderm and the cutaneous ectoderm.
are neural tube defects more common in males or females?
females
folic acid
- by how much do they reduce rates of NTDs
- which are the best supplements
- what is recommended in England
• Folic acid supplements reduce the rates of neural tube defects by 70%.
It is better to take supplements which combine the naturally occurring folates: folinic acid and THF.
• In England it is currently recommended that;
To prevent first occurrence of an NTD women should take 400μg of folic acid daily before conception and during the first 12 weeks of pregnancy.
To prevent recurrence of neural tube defect the dose should be 4 to 5 mg per day.
what drugs taken during pregnancy increase the risk of NTDs in the foetus?
examples:
- sodium valproate (antiepileptic drug)
- folic acid antagonists such as trimethoprim
how are NTDs diagnosed prenatally?
- The fetal liver is the main source of α-fetoprotein (AFP), which leaks through open neural tube defects into the amniotic fluid and then into the maternal blood.
- This abnormal increase in maternal serum α-fetoprotein is best detected at 16 to 18 weeks of pregnancy.
- Maternal serum screening does not detect closed defects (those covered by skin) and is less sensitive in women taking the antiepileptic drug sodium valproate.
• Ultrasonography is recommended for all at-risk women and those with positive serum α-fetoprotein screening, those who have had one or more affected child, and those taking drugs associated with neural tube defects in the fetus.
- However, occasionally spina bifida may not be diagnosed, particularly in the L5-S2 region. Diagnostically, the ultrasonographer is on the lookout for the lemon sign.
- When adequate ultrasound images cannot be obtained, amniocentesis with measurement of α-fetoprotein and assay of neuronal acetylcholinesterase provides an alternative method of prenatal diagnosis.
from what week can anencephaly and spina bifida be detected from?
- Anencephaly can be detected from the 12th week.
* Spina bifida can be detected from 16 to 20 weeks.
what are the lemon and banana signs?
ultrasound features of the Arnold-Chiari malformation in foetuses with open neural tube defects
what does the banana sign refer to?
the shape of the cerebellum owing to caudal (tail) displacement
what does the lemon sign refer to?
the lemon-shaped head, resulting from scalloping of the frontal bones
lemon sign
- what does it have a strong association with
- pathogenesis
- what happens as the foetus matures
- when is it present up to?
The lemon sign has a strong association with spina bifida.
Although the exact pathogenesis is unknown, it has been postulated that the decrease in the intra’spinal’ pressure (due to the failure of closure of the posterior neuropore)in neonates with spina bifida causes the brain to shift downward.
This shift decreases the intra’cranial’ pressure, which is reflected onto the fetal cranium.
The frontal bones are the most vulnerable to the decreased intracranial pressure and respond by flattening or scalloping inward.
As the fetus matures, the lemon sign disappears because the frontal bones become stronger and are able to withstand the decreased pressure.
(The majority of neonates with spina bifida develop hydrocephalus as they mature.)
This increase in intracranial pressure can lead to reversal of the flattening.
The lemon sign is only present up to 24 weeks
what are the Arnold-Chiari malformations?
congenital disorders in which there is distortion of the base of the skull with protrusion of the lower brain stem and parts of the cerebellum through the foramen magnum
- there is a downward displacement of the lower cerebellum, including the tonsils
do Chiari malformations cause symptoms in childhood? what are they associated with? what does it often manifest as?
- It rarely causes symptoms in childhood
- But may be associated with hydrocephalus and syringomyelia
- It often manifests with headaches and cerebellar symptoms and neck pains
what are the four types of Chiari malformations?
- Type I:
This is the only type that can be acquired.
Characteristic of headaches. - Type II:
This is associated with lumbosacral myelomeningocele.
Clinical features include paralysis below the spinal defect. - Type III:
This consists of a downward displacement of the cerebellum into a posterior encephalocele.
This type is exceedingly rare and generally incompatible with life. - Type IV:
This is a form of cerebellar hypoplasia.
what is treatment of Chiari malformations?
Posterior fossa decompression surgery is performed on adults with type 1 & 2 malformations to create more space for the cerebellum and to relieve pressure on the spinal column.
what should patients be evaluated for before a lumbar puncture?
The patient should be evaluated for evidence of elevated intracranial pressure prior to a lumbar puncture, and the safest practice is to perform a CT scan first to avoid risk of herniation.
describe how a lumbar puncture procedure is performed. what can it be used to measure?
A hollow spinal needle is introduced through the skin with a stylet occluding the lumen to prevent the introduction of skin cells into CSF during needle insertion.
Note that the lumbar cistern is normally in direct communication with CSF in the ventricles and CSF flowing over the surface of the brain.
The procedure may be done in the lying or seated position.
A manometer tube is used to measure CSF pressure. Pressure measurements are more reliable in the lying position because in the seated position the entire column of CSF in the spinal canal adds to the pressure measured in the lumbar cistern. Normal CSF pressure in adults is less than 20 cm H2O.
where is the spinal needle generally inserted? why is this? what serves as a landmark for this?
- Note that the bottom portion of the spinal cord, or conus medullaris, ends at about the L1 or L2 level of the vertebral bones, and the nerve roots continue downward into the lumbar cistern, forming the cauda equina.
- To avoid hitting the spinal cord, the spinal needle is generally inserted at the space between the L4 or L5 vertebral bones.
- As the tip of the needle enters the subarachnoid space, the nerve roots are usually harmlessly displaced.
- The posterior iliac crest serves as a landmark to approximate level of the L4–L5 interspace.
what are different types of cranial dysraphism?
- anencephaly
- cephaloceles
- holoprosencephaly
anencephaly
- what is it
- survival
- what associated with
- screening
- treatment
- This is the partial or complete absence of the bones of the rear of the skull, the meninges, and cerebral hemispheres of the brain.
- The absent brain is sometimes replaced by malformed cystic tissue, which may be exposed or covered with skin.
- It occurs as a developmental defect, and most affected infants are stillborn; if born live they do not survive for more than a few hours/days/weeks.
- Anencephaly is often associated with other defects of the nervous system, such as spina bifida.
- Prenatal screening tests for anencephaly include detection of alpha-fetoprotein levels and ultrasound.
- Treatment is supportive.
cephaloceles
- what is it
- what are the subtypes
- how common
- what associated with
- treatment
• This is a herniation of cranial contents through a skull defect.
• There are several subtypes:
1. Cranial Meningocele: contains only meninges.
2. Encephalocele: contains brain tissue.
3. Ventriculocele: contains part of the ventricle within the herniated portion of the brain.
• Cephaloceles are less common than anencephaly or spina bifida.
• They are associated with other brain abnormalities such as agenesis (failure of development of an organ) of the corpus callosum or abnormal gyration.
• They may be part of a recognised syndrome, so it is important to look for abnormalities in other parts of the body.
• Sometimes neurosurgery is indicated.
• Posterior Cephaloceles:
Most common group of Cephaloceles in Western countries and most are occipital encephaloceles.
• Anterior Cephaloceles:
More common in some parts of Asia.
holoprosencephaly
- what is it
- what caused by
- treatment
- This occurs when the embryonic Prosencephalon does not undergo segmentation and cleavage (into telencephalon and diencephalon).
- The anterior midline brain, cranium, and face are abnormal.
- This malformation may be caused by defects of the sonic hedgehog gene.
- Severely affected foetuses may die before birth.
- Treatment is supportive.
what can spina bifida be divided into?
Spina bifida occulta, which consists of failure of closure of the vertebral arches without an external lesion.
Spina bifida cystica in which there is a cystic lesion on the back. The lesion may be either a meningocele without neural tissue or a myelomeningocele in which the spinal cord is a component of the cyst wall.
