009 + 010 development of the brain Flashcards
what is the derivative of the nervous system?
neural ectoderm
what does neural ectoderm form?
neuronal populations e.g. motor neurons, sensory neurones, interneurons
- neuronal support cells = glia e.g. astrocytes, oligodendrocytes, Schwann cells, ependymal cells (lumen of neurodevelopment tube)
- microglia (immune cells)
what is the pathway of ectoderm through development?
ectoderm –> neural plate, neural crest and epidermis
neural plate –> CNS –> motorneurons, interneurons and glia ( astrocytes, oligodendrocytes)
neural crest –> PNS –> sensory neurones, enteric neurons and glia (Schwann cells)
neural crest –> facial cartilage, adrenal medulla, melanocytes and adontoblasts
epidermis = hair, nails, sweat glands, lens, cornea
what is the neural plate and what does it form?
- neural plate = a collection of stem cells (no neurons) destined to form the CNS, thickened portion of ectoderm along midline of the embryo, folds into the neural tube
- forms the CNS = motorneurons, interneurons, glia (astrocytes and oligodendrocytes)
- from ectoderm
what is the neural crest and what does it form (overview)?
- collection of stem cells (no neurons) destined to form the PNS, originate at margins of neural tube
- forms PNS and facial cartilage, adrenal medulla, melanocytes, adontoblasts…
- PNS –> sensory neurons, enteric neurons, glia (Schwann cells)
what is gastrulation?
occurs in the first 3/4 weeks
- forms the 3 germ layers (ectoderm, mesoderm, endoderm
- mesoderm cells ingress through the primitive node to form prechordal plate and notochord
- mesoderm cells ingressing through the primitive streak form paraxial, intermediate and lateral plate mesoderm (not neural related)
( from bilayer epiblast and hypoblast to trilayer )
how does the neural plate form?
- formed by cells that remain in the epiblast later (ectoderm)
- anterior to node and directly above the notochord and prechordal plate
- it expands as primitve streak regresses causally
- 50% of ectodermal cells are found here
- goes on to form the neural tube
what is linear restriction in terms of neural plate?
mesoderm signals to ectoderm above them to linear restrict them to only form CNS and PNS
- left over ectoderm that doesn’t receive the signal forms epidermis
what is the Spemann-mangold organizer?
- they did an experiment with grafting a notochord precursor cells ontp the opposite sides of an embryo
- conjoined twins form
- the implanted cells do not form 2 nervous systems, but they form 2 notochords which instructs the body to have a 2nd head
- this suggests that the neural tube had been induced by the dorsal mesoderm
- same across lots of animals
what is neural induction?
- the nervous system is induced in ectoderm bu the node and dorsal mesoderm (notochord and prechordal plate)
- the notochord induces the spinal cord and hind brain
- prechordal plate induces midbrain and forebrain
what does the notochord induce?
the spinal cord and hind brain
what does the prechordal plate induce?
- midbrain and forebrain
give some examples of signaling molecules that the node and dorsal mesoderm secrete to induce ectoderm
- fibroblast growth factor (FGF)
- chordin
- noggin
- follistatin
- cerberus
- Dkk1
- FrzB
what are the 4 molecules secreted by the node and dorsal mesoderm that inhibit bone morphogenic proteins?
chordin, noggin, follistatin, cerberus
what do chordin, noggin, follistatin and cerberus all do?
- inhibit bone morphogenetic proteins (BMP)
- these are signals that promote epidermal differentiation during gastrulation ( so these molecules inhibit epidermal induction to increase neural induction)
- they are all required for neural development
what are the 3 signalling molecules that inhibit Wnt proteins?
- cerberus
- Dkk1
- FrzB
what do cerberus, Dkk1 and FrzB all do?
inhibit Wnt proteins
- these are signals that promote caudal development during gastrulation
what is BMP?
bone morphogenetic proteins, which signals promote epidermal differentiation (not neural) from ectoderm
what is neurulation?
- process where the neural plate folds along the midline, bringing the lateral edges together to form the neural tube
- the edges zip together from the middle outwards to both rostral and caudal ends
- the edges of the epidermis now also fuse, placing the neural tube inside the embryo
- occurs in 4th week of development
what are the 2 main neural tube defects?
anencephaly (rostral/cranial)
spina bifida (caudal )
what is anecephaly?
- neural tube defect
- when the rostral/cranial part of the neural tube fails to close, so the brain is underdeveloped and protrudes out of head
- usually miscarried or stillborn
what is spina bifida?
- most common neural tube defect
- when the caudal part of the neural tube fails to close to the spinal cord is not fully enclosed/protrudes in the lower back
- can vary in severity, some may have very little problems, whereas some will have nerve damage/paralysis of lower limbs and organs
- most severe = myocele
how many miscarriages (%) are due to neural tube defects?
9%
what can reduce neural tube defects?
- 0.4mg of folic acid daily when trying to conceive can reduce NTD by up to 70%
- some countries now put folic acid in bread and milk to increase entire population levels
what is the neural crest and where is it formed?
- found at the boundary between neural plate and epidermis
- neural crest cells break away from epithelium either before (cranium) or after (trunk) the neural tube is formed
- unique to vertebrates
- forms many different cell types = depends on where migrate in body and what signals exposed to
what do neural crest cells become (specifically-6-)?
- neurons and glia of sensory, sympathetic and parasympathetic nervous systems
- melanocytes
- adrenaline producing medulla cells of the adrenal gland
- aortic pulmonary septum and smooth muscle of great arteries
- facial bones and connective tissue
- odontoblasts (tooth dentin producing cells)
describe the migration of cranial neural crest cells
- they migrate into pharyngeal arches (PA) and frontonasal process (fnp)
- the hind brain is divided into segments called rhombomeres (r)
- neural crest cells from r1 and r2 migrate into the 1st pharyngeal arch
- r4 –> 2nd pharyngeal arch
- r6 –> 3rd pharyngeal arch
- r7 –> 4th pharyngeal arch
M = midbrain, F = forebrain, OV = otic vesicle of ear, E = eye
describe the migration of neural crest cells in the trunk
- neural crest cells will only migrate through anterior half of each somite (sclerotome)
- some remain in the sclerotome and become dorsal root ganglia, while others continue migrating and become support cells, adrenal medulla, sympathetic ganglia…
- dorsal pathway = melanocytes
- ventral pathway = PNS, heart, adrenal medulla
what is the hindbrain segemented into?
- rhombomeres
what parts of the hind brain do neural crest cells migrate into which pharyngeal arches?
- r1/2 = arch 1
- r4 = arch 2
- r6 = arch 3
- r7 = arch 4
what are the 2 pathways of trunk neural crest cells?
- dorsal pathway = melanocytes
- ventral pathway = PNS,heart, adrenal medulla
what do neural crest cells in the vagal and lumbosacral region of the neural tube form?
- enteric nervous system in the digestive tract
vagal = foregut and then midgut (oesophagus to cecum)
lumbosacral = hindgut( colon to rectum)
what is the enteric nervous system formed by in an embryo?
- migration of vagal and lumbosacral neural crest cells
- vagal = foregut and midgut ( oesophagus to cecum)
- lumbosacral = hindgut (colon to rectum)
what part of the neural crest cells form the foregut and midgut?
- vagal section of the neural tube
what part of the neural crest cells form the hindgut?
- lumbosacral section of the neural tube
what is Hirschsprung’s disease caused by?
- failure of vagal neural crest cells to migrate into a part of the colon, so it lacks enteric ganglia
- (lack of innervation to the gut)
what does Hirschsprung’s disease cause?
- abnormal dilation (megacolon) of part of colon proximal to the constricted aganglionic segment of descending colon
- noticed when baby fails to pass meconium
how is Hirschsprung’s disease treated?
- it can be corrected surgically by removing the aganglionic portion of the gut
at the end of neurulation, what is the basic body plan?
- the nervous system is divided along the rostral-caudal axis into forebrain, midbrain, hindbrain and spinal cord/somites
- the heart / aorta is also starting to form
what are the 3 divisions of the brain during development?
- forebrain (prosencephalon)
- midbrain ( mesencephalon)
- hindbrain (rhombencephalon)
what does the forebrain/prosencephalon subdivide into?
- telencephalon = cerebral hemispheres, basal ganglia, corpus striatum, olfactory bulbs
- diencephalon = thalamus, hypothalamus, retina, epithalamus, subthalamus, pretectum
what makes up the telencephalon?
- cerebral hemispheres, basal ganglia, corpus striatum, olfactory bulbs
what makes up the diencephalon?
thalamus, hypothalamus, retina, epithalamus, subthalamus, pretectum
what does the midbrain/mesencephalon contain?
- tectum, cerebral peduncle
what does the hindbrain/rhombencephalon subdivide into?
- metencephalon (r1-3) = cerebellum, pons
- myelencephalon (r4-7) = medulla oblongata
what is the metencephalon (r1-3) made up of?
(hindbrain )
- cerebellum and pons
what is the myelencephalon (r4-7) made up of?
(hindbrain)
- medulla oblongata
give an overview of brain development in a fetus
- forebrain, midbrain and hindbrain sections formed from neural tube
- the telencephalon (forebrain) expands and soon dominates the brain, until it covered the midbrain and part of the hindbrain (they are all pushed underneath forebrain)
describe the cell division in the neural tube
- the newly formed neural tube is a pseudostratified epithelium of rapidly dividing cells
- nuclei migrate to the other surface for s-phase/dna replication before returning to the ventricular surface
- cells now retract their cellular processes and complete M-phase before restoring cellular processes
- initially, cell divisions are symmetric and produce 2 identical daughter cells that continue to divide
(the moving nuclei make it appear pseudostratified)
describe cell differentiation in the neural tube
- neuroepithelial cells eventually undergo asymmetric cell divisions, producing mitotic cell and non-mitotic neuroblast ( a progenitor cell)
- neuroblasts will produces all neurons in the CNS
- neural tube now becomes stratified into ventricular/bottom(mitotic) mantle/middle (neuronal bodies) and marginal/top (nerve fibre layers
- subsequent waves of mitosis produce glioblasts, which form the support cells of the CNS
- radial glia provide pathways for neuroblast migration within the neural tube
what progenitor cells produce all the neurons in the CNS?
- neuroblasts
what are the 3 layers in differentiating neural tube?
- ventricular, mantle, marginal
what is found in the ventricular layer of the neural tube?
- ependymal cells
- stem cells
- mitosis
- radial glia
what is found in the mantle layer of the neural tube?
- differentiated cells
- neuronal bodies
- glioblasts
what is found in the marginal layer of the neural tube?
- nerve fibers
- top layer = ready to migrate out
describe the pathway of neural progenitors
- progenitor expansion phase = divide symmetrically to produce more stem cells/progenitor cells
- neurogenic phase = radial glia cells divide asymetrically to produce a mitotic radial glia cell and either a neuroblast or a glioblast
- gliogenic phase = the neuroblasts and glioblasts differentiate into neurons, oligodendrocytes, astrocytes and ependymal cells
- radial glial cells differentiate into astrocytes
what is the layering pathway in neural tube differentiation?
- neurons generated in the ventricular zone (bottom) migrate to their final locations along the processes of radial glial cells
- the first wave (blue) migrate the shortest distance, forming the inner most layer of neurons
- the second wave (green) migrates past/above the earlier neuroblasts forming the next layer
- this repeats so the first neurons are on the bottom/inner most and the last are on the top/outermost
how is the spinal cord organised?
- split into 9 distinct layers along the dorsal-ventral axis of the spinal cord called Rexed laminae
- each layer has neurons with specialised functions
- e.g. layer 9 =motor neurons, layer 8 = motor interneurons…
what induces the floor plate of the neural tube?
- the notochord
- it has a key role in patterning the ventral half of the neural tube by inducing the floor plate
- shown by experiments grafting and removing the notochord
what does the floor plate of the neural tube induce?
- motor neurons
- the floor plate is responsible for establishing different neuronal identities in the ventral half of the neural tube (where motor neurons are)
what is the signal that the notochord and floor plate release?
- sonic the hedgehog
what does sonic hedgehog signal released from the notochord and floor plate do?
- it activates the expression of Nkx2.2 in ventral progenitor cells and restricts Pax6 to more dorsal progenitor cells
- Islet1 is expressed by differentiating motor neurons formed by Nkx2.2/Pax6 expressing progenitor cells
- from closest to furthest distance to Shh: Nkx2.2, Islet1, Pax6
closest = activate expression, further = restrict
what specifies neuronal subtypes in the spinal cord ( ventral and dorsal)?
- SHH specifies it in the ventral half of the neural tube
- BMP specifies neuronal subtypes in the dorsal half
what part of the neural tube does SHH specify?
- ventral half
what part of the neural tube does BMP specify?
- dorsal half
what do SHH mutations cause?
- holoprosencephaly
- affects 1 in 250 pregancies but few are born
- in most severe cases the forebrain fails to divide into the double lobes of the cerebral hemisphere
- less severe cases have near normal brains but facial deformities that may affect the eyes, nose and upper lip
- e.g. often have only 1 eye = cyclopia
what is holoprosencephaly?
- often due to SHH mutations
- where forebrain fails to divide into the double lobes of cerebral hemisphere (only has 1 lobe)
- less severe has facial deformities effecting the eyes, nose or mouth (e.g. born with 1 eye, cyclopia)
what does a developing axon grow from?
- axon growing out from a neuron cell body ends in a motile structure called growth cone
describe the development of axons
- the axons growing out from a neuron cell body ends in a motile structure called the growth cone
- many filopodia (finger-like projections) are continually extended and retracted from the growth cone to explore the surrounding environment, to feel for axon to grow towards stable environment
what are filopodia?
- finger-like projections that feel out the environment of the growing axon to guide it to grow in a stable environment
what are the 4 types of mechanisms that control the direction of the growth cone during axon development
- chemoattraction = attractant molecules present as diffusible gradients
- contact attraction = attractant molecules bound to the substratum
- chemorepulsion = repulsive molecules that repel axon growth in diffusive gradients
- contact repulsion = repulsive molecules that repel axon growth are bound
describe the segmentation of spinal nerves during development
- the axons from motor neurons exit the spinal cord via ventral roots but will only migrate through the anterior regions of adjacent somites
- cells of the posterior region express ephrin which is an inhibitor of motor axon growth
- this segments the spinal nerves as it tells motor neurons to avoid the posterior margin
describe the segmentation of the nervous system during development
- motor axons leaving the neural tube form a ventral root, which joins with fibres to the dorsal root ganglion to form a spinal nerve
- both motor axons and DRG are repeated segmentally because they are excluded from the posterior region of each somite
what are commissural neurons?
- neurons found in the dorsal half of the spinal cord and receives sensory signals such as pain, heat or cold
what is the pathway of commissural neurons and what determines their movement?
- they are found in the dorsal half of the spinal cord
- their axons project towards floor, cross the midline and then rostrally to brain
- repellants from the roof plate (BMP) and attractants from the floor plate (Netrin, SHH) are responsible for this directional movement
describe Netrin’s effect on the neural tube floor plate
- RNA for Netrin-1 and Netrin-2 are localised to the floor plate of the neural tube but the proteins diffuse towards the dorsal side, forming a concentration gradient
- this gradient attracts commissural axons towards the floor plate
what happens to commissural axons in the absence of Netrin-1
- most commissural axons do not migrate to the floor plate and fail to cross the midline
