developmental biology of the brain Flashcards
what is gastrulation?
the process where the single layered blastula is reorganised into a trilaminar structure called the gastrula
describe the framework for CNS development
- rapidly dividing ball of cells
- signalling centres develop
- cell mixing restricted
- cells destined to be skin or brain
once a cell is destined to be neural tissue what occurs?
- neurones are generated and they migrate to final position
- glia are produced
- synapses are generated
how many glia are there per neurones?
there are 10 times as many glia cells than neurones
once synapses are generated in the CNS what occurs?
excess neurons are culled
what occurs in the CNS throughout life?
fine tuning
new synapses are formed and neurones are tested to see whether they need to be maintained
what is the neuroectoderm?
it is ectoderm which received bone morphogenetic protein-inhibiting signals from proteins such as noggin, which leads to the development of neural tissue (and not skin)
where do the signal to the ectoderm (to become neuroectoderm) come from?
the axial mesoderm, which is ideally placed under the ectoderm for signalling
what ensure correct neural plate formation? (3)
- signals expressed in correct location
- signals that are produced have the correct cell type inducing ability
- signals expressed at the correct time
what is BMP4?
bone morphogenetic protein 4 is a pro-epidermis and anti-neutralising signal
by default all ectoderm will become skin
this needs to be blocked to form neural tissue
what signals block BMP4? (4)
- Cerberus
- chordin
- noggin
- follistatin
what is the proposed retinoic acid concentration gradients function?
anterior/posterior signalling
high concentration at the head and low at the tail
what signals need to be inhibited to make a head? (3)
- Wnt/B-catenin
- TGF
- BMP
what is the neural plate?
neutrally committed, multipotent stem cells
TF expressed are that of a broad domain, restricting cell potency
why might making a nock-out mouse for a specific TF in neuronal differentiation not make an effect?
the brain is robust, there is lots of redundancy that will compensate for the lack of TF
what TF maintain neural progenitor from differentiating?
Sox 1, 2 and 3
which sox gene is important in fate switching?
Sox2 in neural ectoderm inhibits Oct4
Oct4 drives the formation of mesoderm
what is sox2 also important for?
localisation of the stomach in the gut
Additionally, what is the function of other sox TFs?
to stop stem cell like proliferation and drive neural differentiation
along with special and temporal factors, what else effects gene expression?
gender
why are mouse embryos hard to work with?
they are hard to culture and need to be looked after
can be cultured for a few days in a bioreactor
what can be done to a chick to observe the effect of a TF on nervous system development?
electrophorese a gene into the side of embryo through a window of an egg
the other side of the embryo can be used as a control
why are in utero operations difficult?
can easily trigger a miscarriage
why are Xenopus embryos useful in developmental studies?
embryos are quite large and easy to manipulate
this means they are useful in telling us about the early stages of development
how can the same set of morphogens used in different parts of the embryo produce different tissue?
these signals are acting on cells with different TF profiles. for example, response gene for a signal may be so epigenetically repressed, from a past signal, that there is no response.
what happens if neural stem cells are triggered to leave the cell cycle too early by manipulating factors regulating the cell cycle?
brain formed is too small
what happens if neural stem cells are artificially kept in the cell cycle for too long before leaving?
lots of neurones will end up being culled
how have humans tweaked the cell cycle in the cerebral cortex over evolution?
increased proliferation before differentiation
what does the notochord release to induce the anterior/posterior regionalisation of the neural tube?
Shh
what are bHLH? and what do they do?
a group of pro-neural TFs, they tell neural stem cells to make neurones
what is neurogenin?
a family of bHLH TFs involved in neuronal differentiation
name a localised TF for retinal development
bHLH Ath5
what does oscillations of bHLH TFs maintain?
multipotency
what happens when there bHLH TFs are stably expressed?
differentiation
name a pro-neural gene involved in cerebellum development
math1
FISH can be used to located this marker in early embryonic development
in what order are the brain axes formed?
- anterior/posterior
- dorsal/ventral
- left/right
at what point is the DV axis established
shortly after neural tube closure
what are the three main regions of the brain?
- hindbrain
- midbrain
- forebrain
what do signalling centres release?
local signals/morphogens
name an example of a signalling centre, giving its location
the isthmus is a signalling centre located at the midbrain/hindbrain boundary
what will the hindbrain become?
the cerebellum
where are dopaminergic neurones located?
in the midbrain at the bottom of the neural tube, they project into the forebrain in later development
what happens when you move the location of a signalling centre?
trigger development of the different tissues in the wrong part of the brain
name the two key signals released from the isthmus?
FGF8 and Wnt1
what occur in Oct2 null mice?
they lack anything in front of the isthmus (brain anterior)
what causes DN apoptosis in Parkinson’s?
the production of ROS
what signals the ventral location of dopaminergic neurones?
Shh
what signals the midbrain information of dopaminergic neurons?
FGF8 and Wnts
what is the substantia nigra?
it is the location of DN in the midbrain
it is diminished in Parkinson’s
what happens when SNpc DN die?
tremors and reduced movement
this occurs in Parkinson’s
what is the function of VTA DN?
they are involved in mood control and addition
they are not affected in Parkinson’s
what are radial glia?
they are neuronal stem cells that can form DN and later astrocytes to support DN
what are astrocytes?
star shaped glial cells of the CNS
what’s the additional function of radial glial?
act as scaffold for DN to migrate along
DN exit the cell cycle in the ventricular zone and migrate down RG to ventricle edge
what does cortical hem secrete?
Wnts and BMP
what does cortical anthem secrete and why?
extracellular region of Frizzled recepts, this binds wnt and locally prevents Wnt signalling
control of cell type and number is important. which additional factor is especially important in the layered cortex
migration
which two cell types are important for this migration?
radial glia and Cajal-retzius cells
what is the function of Cajal-retzius cells?
they are not entirely understood but seen to be essential in stopping cell migration
what is microcephaly?
congenital condition associated with incomplete brain development
which virus is suggested to be causing microcephaly?
Zika virus
this is additionally associated with additional neuronal cell death and even fewer neurons
what is used to model microcephaly and show links to Zika?
cerebral organoids
these have organisation much like the cerebral cortex
what causes reduced neurone production in microcephaly?
incorrect spindle orientation resulting in not enough symmetrical division of radial glia
how many layers are there in the neocortex?
6
they are not completely independent and need to be in the correct order for function
what percentage of neurones in the neocortex are excitatory? name the one type that is inhibitory
80%
GABA interneurons
which layer of the cortex is generated first?
the deepest layer
newly generated neurones crawl past these to form upper layers towards meninges membrane guided by radial glia
what causes lissencephaly?
a disorder of cortical migration caused by cells not responding correctly to signals and dysfunctional cytoskeletons, resulting in missing/disordered layers of the cortex
what is reelin?
protein released by Cajal-retzius cells signalling cells to migrate toward these cells
what recent discovery was made about oligodendrocytes using single-cell RNA-seq?
there are 5 types of oligodendrocytes (cells which myelinated neurones), these are the cells which are attacked in MS
what causes radial glia cells to produce astrocytes and not DN?
methylation of pro-neural genes histones
what is the Blue Brain Project?
they are trying to map the human connectome in order to be able to engineer a novel system
