Brain Development Flashcards
What layer does neural tissue come from
midline ectoderm
What is neurulation
The folding of the neural plate to form the closed
neural tube
what do defects in neurulation lead to
how common is this
neural tube defects (NTDs) and are fairly common (~1 in 500 live births) – e.g. spina
bifida occulta and the severe complications of myelomeningocele (open spina bifida)
What forms the PNS
neural crest cells
NCCs emigrate from dorsal neural tube into the embryo and generate most peripheral neurons and all peripheral glia: all autonomic ganglia (sympathetic, parasympathetic, enteric), almost all somatosensory neurons (all in dorsal root ganglia, most in trigeminal ganglia, all in ‘superior’ ganglia of cranial nerves VII, IX, X)
Where does most of the PNS in the head arise from
cranial neurogenic placodes (paired patches of thickened embryonic head ectoderm)
What do the cranial neurogenic placodes form (5)
olfactory epithelia (cranial nerve I);
eye lenses; inner ears & their afferent neurons (cranial nerve VIII);
lateral line organs and afferent neurons (fish, amphibia only);
some somatosensory neurons in trigeminal ganglia (cranial nerve V);
all taste & viscerosensory afferent neurons in ‘inferior’ ganglia of cranial nerves VII, IX, and X
How is the anterior posterior axis of the brain developed
Neural tissue becomes regionalized under the influence of external signals, establishing domains of expression of different transcription factor genes
What are signaling centres in the brain
act as ‘organisers’ by secreting factors that influence the fate of nearby tissue
give an example of signalling centres in the brain
midbrain/hindbrain boundary or isthmus develops at the boundary between expression domains of two different TFs (Otx2 in forebrain and midbrain; Gbx2 in hindbrain).
The isthmus secretes FGF8, which patterns the tectum anteriorly and induces the cerebellum posteriorly, in the dorsal part of rhombomere 1
Ventrally, FGF8 acts with Shh (secreted by the ventral midline) to induce dopaminergic neurons in the Otx2+ midbrain and serotonergic neurons in the Gbx2+ hindbrain
What are rhombomeres?
hindbrain segments
True or false
due to its complex structure, lots and lots of secreted factors are required for the brain’s development
false
Cells expressing different TFs can respond differently to the same secreted factor(s). So, relatively few secreted factors - FGFs, BMPs (‘bone morphogenetic proteins’), Wnts, hedgehog proteins (e.g. Shh), retinoic acid – can be used at different times in different regions to specify the huge diversity of neuronal cell types
What are the key secreted factors controlling brain development (5)
FGFs, BMPs (‘bone morphogenetic proteins’), Wnts, hedgehog proteins (e.g. Shh), retinoic acid
What is cell identity along the A-P axis patterned by the hindbrain and spinal cord/
different combinations of Hox genes
What controls expression of Hox genes
opposing gradients of retinoic acid and FGF8 secreted by the paraxial mesoderm
What are Hox genes important for in CNS development
regional neuronal identity, axon guidance and circuit formation (shown e.g. by mouse gene knockouts)
What controls development of the dorsoventral axis
notochord acts as a signalling centre at the ventral midline, inducing the neural tube floorplate via secretion of Shh.
The floorplate in turn acquires signalling properties, including Shh expression, and patterns the D-V axis of the spinal cord.
The highest concentration of Shh induces floorplate; lower concentrations induce motor neurons and suppress dorsal spinal cord neuronal phenotypes (Shh acts as a morphogen).
The dorsal neural tube is patterned by an opposing gradient of proteins secreted from the roof plate
How are the neural tube cells initially arranged
as a neuroepithelium, with multipotent stem cells dividing in the ventricular zone (VZ).
What do the multipotent stem cells in the VZ of the neural tube form
generate neurons
also form radial glia which provide an important scaffold for neuroblast migration (e.g., ‘inside-out’ development of the cerebral cortex)
What happens to neuronal stem cells in mammals
what does this mean for production of neurons later in life
disappear later in development (probably differentiating into astrocytes) except in a few specialized locations (e.g., hippocampus, olfactory bulb).
Production of neurons ceases in infancy in most regions of mammalian brain, and all neurons are post-mitotic.
What does ‘amoeba on a leash’ refer to
the growth cone
What does the growth cone do
navigates using actin/myosin interaction to promote motility heading forwards as long as it has a suitably adhesive substrate and is not deflected;
progress is regulated by adhesion and signalling
embryonic
neuroepithelium is highly patterned molecularly, so growth cones successively encounter different cues. These regionally distinct ‘intermediate targets’ act as ‘stepping stones’, guiding axon growth towards the final target.
How do axon scaffolds change over time
established when distances are small. Complexity builds up over time: a progressively elaborated axonal scaffold builds on the earliest axonal pathways
What are the 4 general classes of molecules that guide growing axons
diffusible attractive
diffusible repellent
contact attractive
contact repellent
Give 2 examples of diffusible attractive molecules that guide growing axons
NGF (nerve growth factor - a neurotrophin family member),
netrin
What are the 2 different things a diffusible attractive molecule can be
neurotrophic (‘nourishing’, promoting survival and sprouting of neurons),
neurotropic (‘attractive’, promoting chemotaxis of growth cone - chemoattraction)
Give 2 examples of diffusible repellent molecules that guide growing axons
eg. semaphorins, Slit
What are growth cone CAMs
cell adhesion molecules
they made adhere to
a) large proteins in extracellular matrix (eg. laminin, fibronectin);
b) the same CAM on a neighbouring cell (homophilic adhesion);
c) another CAM on a neighbouring cell (heterophilic adhesion).
Intracellularly, CAMs connect both to the cytoskeleton and to cytoplasmic signal
transducers (eg. tyrosine kinases).
What is homo- and heterophilic adhesion
when growth cone CAMs adhere to the same CAM on a neighbouring cell (homophilic) or another CAM on a neighbouring cell (heterophilic adhesion)
Give 3 examples of contact repellent molecules that guide growing axons
eg. Semaphorins, Ephrins (bind Eph receptors) and some proteoglycans.
Do growth cones only respond to chemical cues?
can also respond to mechanical cues
Retinal ganglion cell axons are more exploratory on soft substrates and more directionally persistent on stiff substrates. They turn away from
stiffer tissue and grow towards softer tissue in vitro and in vivo.
Stiffness correlates with cell density.
Where do the different parts of the retina map to in the tectum
temporal (posterior) retina -> anterior tectum;
nasal (anterior) retina -> posterior tectum;
dorsal retina -> ventral tectum;
ventral retina -> dorsal tectum
Describe the experiment Sperry used to demonstrate the chemoaffinity hypothesis
what did he propose
In goldfish and adult frogs, Sperry cut the optic nerve & excised half of the retina; axons from the remaining half-retina always regenerated to the correct half-tectum.
Sperry (1963)
proposed the existence of separate chemical gradients in retina and tectum, providing a “chemical code with matching values between the retinal and tectal maps”.
How did Friedich Bonhoeffer use the retinotectal system
to identify membrane-associated ephrins and their Eph receptors.
Counter-gradients of ephrins and Ephs in the retina and tectum provide contact-repellent and also contact-attractive cues for patterning
