Lecture 2 - Development of NS II (Neurogenesis, Migration and Brain)

neural tube

cells that make the walls of the neural tube will continue to divide, migrate and later make connections, expanding the CNS, the lumen will form the ventricles of the brain allowing CSF, spina bifida or anencephaly can result from improper closure of the neural tube depending on if its on the rostral or caudal side

prenatal brain development

during beginning of neural tube formation, assuming we get complete closure, by 100 days post conception the brain begins to have initial appearance similar to adult brain, although cellular structure and myelination is not complete by 9 months very similar in appearance to adult

lissencephaly

smooth brain, no folds

sulci and gyri

develops at the 7 month mark, brain fully develops by 32, last steep drop off by 83

origin of brain cells in the adult

during embryonic development, all cells divide and are capable of self renewal, however some cells within the neural tube soon lose this capacity and will form other cell types and become specialized, progenitor cells can divide, blasts are dividing cells with limited ability to divide and only for restricted periods pf time,

blasts

produce neuroblasts which form neurons and glioblasts which form glial cells, these cells allow for further growth and differentiation, they are dividing cells with limited ability to divide relative to progenitor and stem cells, only restricted for restricted periods of time

specialized cells

this is when neural cells terminally differentiate into interneuron and pyramidal neurons while glial cells differentiate into oligodendroglia and astrocytes, this means cells can’t divide anymore

inductive signals

these signals act locally on either the ventral or dorsal neuroepithelium of the neural tube to produce distinct patterns of gene expression and ultimately, differentiation of specific classes of neurons, the signals affect stem, progenitors and blast cells,

sonic hedgehog (shh)

peptide hormone, most important ventral signal of developing neural tube, its produced by both the notochord and floorplate,

roofplate and dorsal ectoderm inductive signals

includes a variety of signals including dorsalin and other members of the TGF family as well as nogging and retinoic acid which is produced by dorsal surface as well, concentration gradient goes down the neural tube

adult neurogenesis

scientists published studies suggesting that stem cell existed in the adult brain, similar to stem cells in developing brain this requires a number of factors to aid proliferation, the adult ones, it slows down ageing and may even be slower in neurodegenerative conditions like alzheimer’s and dementia, in adult brain if you damage it there is no regrowth cause no stem cells are left

prolactin (PRL)

23-k-Da protein hormone that binds to a single span membrane receptor, a member of the cytokine receptor superfamily and exerts its action via several interacting signaling pathway, its a multifunctional hormone that affects multiple reproductive and metabolic functions and is also thought to be involved in tumorigenicity, not only is it a classical pituitary hormone but it also acts as a cytokine

how does prolactin promote neurogenesis?

it acts to promote physiological responses related to reproduction, stress adaptation, neurogenesis and neuroprotection so the more prolactin there is the more neurogenesis there is, it contributes to a wide array of changes that occur in the female brain during pregnancy

Weiss group paper on prolactin

found prolactin was shown to increase the number of new neurons suggesting that hormones and other proteins could be used to control neurogenesis

BrdU + EdU

as cell divides you have to double the DNA, it can introduce at thymidine analogue/look like it gets incorporate into daughter cells which would indicate presence of BrdU and EdU proving cell division occurs, we want to see if we can detect new DNA that uptook the analogue, mature cells normally not dividing so don’t uptake BrdU

where is BrdU and EdU located?

in the dendate gyrus of the hippocampus

BrdU microscopy study

used to show that BrdU is actually found in the cell nucleus to confirm cell is dividing, it can colocalize it, the more of it present the more cell division/neurogenesis there is

gene expression

occurs as per adult neurogenesis/stem cells, turning on and off key genes in stem cells during development is critical in ensuring formation of neurons vs glia, many different chemical signals have been shown to be important in cell fate during brain development, for instance a chemical signal or protein must induce the stem cells to form progenitor cells and then other signals act on progenitors to produce neuroblasts or glioblasts

growth factors

includes neurotrophic factors and epidermal growth factor (EGF), they are more widespread relative to inductive factors

epidermal growth factor

when stem cells are exposed to it they will form more progenitor cells, it allows for proliferation and expansion of neural progenitor/stem cell populations, other types of neurotrophic factors like the family of fibroblast factors are added to progenitor cells in vitro and will be induced to form more neuroblasts so they push developmental genetic programs to form more neuroblasts, especially basic fibroblast growth factor (bFGF or FGF-2)

bFGF or FGF-2

role is its a key mitogen that maintains or expands neural progenitors so the more FGF-2 there is the more neuroblasts, so it pushes progenitors to form neuroblasts

radial glia like cells (type 1)

remains as stem cells, now found in the dentate gyrus and subventricular zone, markers include GFAP (also for astrocytes), Nestin, Sox2 and PDGFRA, they are found mostly in the brain and we want to push them to become neurons

intermediate neural progenitor cells (Type 2)

they are still capable of cell division, marked by some of the markers that are very similar to stem cells, less likely to divide, has to be pushed to do it, they could form glioblasts too

progenitor cell markers

EdU and Nestin +

NeuN

marker found only in mature cells

astrocyte markers

markers include GFAP and S100B, need to see both for 100% confirmation

oligodendrocyte markers

need to have MBP and S100B

glial progenitor markers

need to have at least Olig2 and S100B, additionally also Ascl1, Sox2, PDGFRA, NG2 and NES

growth + development of neurons

human brains have around 10 billion neurons in the cortex per hemisphere, doesn’t account for brainstem or cerebellum just cortex, it has been estimated that at the peak of prenatal brain development to create this number we would require 250k neurons to be born each minute, this means lots of cell division and maturation, there also has to be room created and neurons have to migrate or travel to the correct location to fully form, at the correction spatial coordinates they need to undergo synaptogenesis

synaptogenesis

making new synapses, if it goes wrong, it could cause nervous system issues and lead to developing things like SCZ

how does neurogenesis work?

neuroblast formation is important as it forms the precursor to more specialized neurons, it allows for migration as well as spatial signals to determine what specific groups of neurons they will become if they move to the right location/final destination, radial glial progenitors will contact the CSF so expansion + cell migration starts to happen

embryonic neurogenesis

first there is neurulation at conception, then once the neural tube is formed this leads to neurogenesis starting with microglial entry which comes from yolk sac, its not normally part of stem cells but it comes from epiblast cells, then this causes synaptogenesis, apoptosis, gliogenesis unlikely going to be astrocytes or glial cells undergoing it but rather other cells instead

cerebral palsy

its one of the most common neurodevelopmental motor disorders, its a non progressive motor disorder linked to brain injury, its a clinical term used to describe a spectrum of movement and posture disorders resulting from non-progressive disturbances in the developing fetal brain, this is a big reason why ppl worry about premature child birth,

cerebral palsy epidemiology

the disease is caused by a mix of environmental and genetic causes, it causes intellectual disability, social autism, vision, speech and seizure epilepsy, it is caused by movement issues due to damage in the cerebellum and basal ganglia