BIOL 2052 - Brain development

stages of brain development

• neurogenesis

• migration

• differentiation

• target innervation

• synapse formation

neurogenesis

• creation of neurons

• occurs during the first 18 days of development

• a plate like structure formed which has 3 germ line layers

• ENDODERM: gives rise to the lining of the digestive tract and organs

• MESODERM: gives rise to the muscle, skeleton, circulatory system

• ECTODERM: gives rise to the skin and brain —> from the neuroectoderm the neural plate is formed which gives rise to the whole nervous system

• the notochord is formed at the midline

• After formation of the neural plate it folds inwards and closes forming the neural tube

• the neural tube at one end gives rise to the brain, whilst at the other end gives rise to the spinal chord

• the lumen of the tube will become the ventricles which hold the CSF

• where the tube closes is called the roofplate

• the floorplate is found above the notochord

• the notochord, floorplate and roofplate are transient structures which are important for instructing the nervous system

• the neural crest will then separate from the neural tube and will give rise to the PNS

patterning in the neural tube

• anterior and posterior regions along the length of the tube

• dorsal and ventral along the cross section of the tube

• proliferation and segmentation determines the early spinal chord and forms 3 primary vesicles, the brainstem, midbrain and the forebrain

• patterning and differentiation of cells is determined by morphogens

differentiation

• when and where a neuron is born will determine its ultimate fate

• differentiation is driven by morphogen gradient

• morphogens bind to receptors to activate or repress transcription factors

• gene expression profiles determine the cell identity

• the response of the cell is determined by

  • availibility of ligand

  • Prescence of receptors

  • distance from secreting cell gradients

EXAMPLES:

• cells in posterior secrete and produce less wnt and BMP compared to cells in the anterior

• at the roofplate high expression of BMP, low Shh, whilst at the floorplate high Shh and low BMP

• gene expression during development is so tightly controlled that receptor must be already expressed before the morphogen is secreted

hox gene

• family of transcription factors

• in human have A-D

• hox helps to establish segmentation of anterior and posterior axis

how do we know cell fate can be induced

• graft of tissue from pigmented to non amphibian embryo

• secondary neural tube is developed with a mixed origin

• transplanted cells instructed by genes but also by the cells arund them

migration

• how neurons get to the correct place

• cells use the scaffold of the ECM to migrate

• neuroblasts migrate to the pial surface

• they migrate from the marginal zone vertically and they differentiate into neurons

• newer neuroblasts migrate past they older cousins to the cortex is built indie out

• EXAMPLE: building the cortex

• neuroepithelial progenitor cells in the neural tube are the neural precursor cells

• the neural precursor cells form the ventricular zone

• the radial glia connect the ventricular and pial surface and they divide slowly and symmetrically

• the precursor cells divide asymmetrically in the ventricular zone (transit amplifying cells)

• these generate new progenitors and post mitotic neuroblasts (they dont divide and give rise to neurons)

symmetric vs asymmetric division

RADIAL GLIA

• dividing cells will give rise to identical cells

• new cells provide more cells to expand that region

• radial glia will undergo symmetric and asymmetric division but will form at least 1 ore radial glial cell with each division

NEUROBLASTS

• dividing gives rise to different cell types which will have a different role and will migrate to a different area

origins of glia

• generated from the neuroepithelium

• glioblasts either

  • remain attached to the epithelium

  • become ependymal cells which produce CSF

  • move to the marginal layer and become astrocytes involved in the maintenance and repair o oligodendrocytes

interneurons

• have an inhibitory function rather than being an excitable neuron

• have a different origin —> born in the ganglionic eminences

• migrate tangentially at the periphery

target innervation

• neurons must polarize: reach in all directions and axons and dendrites are established

• processes use cues and signals to help them navigate

• or a group of neurons will fasciculate - piggy back eachother and travel in a buncle with already developed neurons

how do axons find their target neurons

• motor neurons have a clear target of where they must innervate

• they have stops and checkpoints on the way to their destination and they use cues and signals to help them navigate called guidance signals

• guidance signals can be both attractive and repulsive and can be short range or long range

• guidance signals are interpreted by the growth cone which is a structure in the axon

• if a guidance signal is chemo repulsive the growth cone will collapse and the process will not be able to grow further —> no longer see this as a target

TYES OF GUIDANCE SIGNALS

NON DIFFUSABLE

• short range

• substrate derived

• in ECM or presented on the target cells

• cadherins or ephrins

DIFFUSABLE

• act as gradients

• long range/short range

• netrin and semaphorins

contact mediated repulasion

• when fasciculation occurs the other axons will continue to produce chemo attractive signals until the growing axon needs to separate out

• in which case chemo repulsive signals sent out and a new axon branches out and forms a growth cone

how are signals sensed

• growth cone structures have filopodia and lamellipodia which have receptors on their surface which sense guidance cues

• they have cytoskeletal proteins actin and microtubules which allow them to reach out once the direction has been determined

EXAMPLE: commissural neuron

• DCC talks to netrin 1 in a long range attraction process

• when the neuron gets close to the floorplate NrCAM attracts the neurons which is detected by TAG1 in a short range attraction

• short range repulsion of the neuron slit is detected by Robo

why dont neurons cross?

• motor neurons follow guidance signals and exit the cell to reach out to target muscle tissue

• therefore, they travel outside the cell

synapse formation

• mediated by synaptic cell adhesion molecules

• molecules which help maintain the connection between synapses

• neurexins (NXN) expessed in the presynaptic terminal which interact with the neuroligands in the postsynaptic terminal

• several cell adhesion molecules will hold together the synapses

• neuroligands on the postsynaptic terminal will recruit other entities which will detect the release of neurotransmitters so helps relieve the signal

abandoning synapses

• some synapses kept, some abandoned

• neurotrophins and electrical activity determine the final pattern of the contacts

• not only are synapses abandoned when theyre not used but cells are abandoned too

• axons which have more activity will become more stabilised as the binding of neurotransmitters and calcium signalling molecules cause more electrical activity therefore more stable

• axons frequently used together will come together to form neural circuits