Lecture 3 - Cell Migration and Inductive Signals

cell migration

begins shortly after the first neuroblasts are generated and continues for about 6 weeks in the cerebral cortex, it continues beyond this point in areas like the HPC which take longer to develop, when cells find their appropriate areas to migrate to, they differentiate into the appropriate neurons

radial unit hypothesis

start with flat sheet, then neural sheet + groove, thickens forming different layers, the cortex is organizes into layers (3 in rodents and 6 in humans), the neurons of each layer are distinct and have different properties and types of neurons and they know where to go by radial unit and cortical mapping acting as a protomap

radial glial cells

found in the subventricular zone, full on stem cells act as a guide for nervous system growth (they grow together) allowing nervous system extension, they act as guide raide for migration + progenitor cells so they can form neuroblasts + other cell types,, the basement membrane is where the cell bodies of thesecells are located, some maturation wont end until after the post natal stage cause full on brain maturation after age 32, developing neurons use radial glia to climb up to the riht area, cant get to the right area w/o guide rails from radial glial cells

subventricular zone

contains a primitive map of the cortex that directs cells to their appropriate location in the cortex, one region of it may contain cells that will migrate to form the visual cortex while a different region may have cells that form the frontal cortex, they can then map where the cells migrate

how do cells know where to migrate to?

the radial glial cells found in the subventricular extend one process to the cortical surface, as the brain continues to grow these glial processes can continue to grow,

human transketolase like protein 1 (TKTL1)

increases the number of basal radial glia in modern humans and thereby the output of upper layer projection neurons, the mouse one only makes 3 layers associated with the cortical plates, in neanderthal arginig creates more layers and for humans its histidine that allows us to have more radial glial cells/faster cell division of them

pentose phosphate pathway (PPP)

allows glucose conversion to ribose for nucleic acid synthesis, glucose degradation to lactate and regeneration of redox equivalents

migration patterns

stops at lowest 1st layer then other cells climb over top of it, cortical layers develop from the inside out, neurons of the innermost layer IV migrate to their locations first followed by those destined for layer V, later arriving neurons pass by earlier arriving neurons, likely happens through chemical patterns and signals available in the extracellular matrix of the migrating neurons

how does neuronal migration start?

the neurons migrate to their final destination using a number of different gene expression changes and proteins in the extracellular environment so it gives the differentiation signal, neurons then need to grow dendrites to receive synaptic connections and extend axons to make synapses with other neurons/networks, neural maturation involves both dendritic formation which in turn involves arborization, dendrite formation begins prenatally but continues in the first few years of life, additionally spines on dendrites must start to form as well

dendrites in neural migration

they grow 1-2 micrometers per day during development, at the same point in time axons may grow millimeters per day, axons and the growth of axons may be able to help form dendrites because they grow faster and may release other factors that allow arborization, visual, language and more neuronal connections follow this patterns, we have long axons being formed after completion of migration

axons

growing by millimeters, get pushed out faster than dendritic arborizations

growth cones

they are growing tips on axons known as axon extensions, they are trying to figure out what molecules around it they are interacting with, the ends allow for filopodia involving actin being an extension of it, they interact with various molecules like CAMs and tropic molecules (ex: netrin with steers growth cone to where the axon needs to get to

synaptic pruning

synapses that eventually cause neurotransmitter release and in some areas of the brain continue to increase until 1 year after birth (visual cortex), elimination via microglial cells using complement activation (C1q/C3) that express CR1, this only interacts with neurons and synapses that are not active

microglia

act like macrophages during synaptic pruning, this creates protrusions where they have interactions with different synapses, they are derived from yolk sac, neuron converts C1q to C3 on developing neuron

CR3

binds to C3 and eliminates synapse

neuronal cell death

neurons that make appropriate connections are thought to survive cause they have access to neurotrophic factors, if not they are going to need specific factors to make them healthy, the growth factors which support neuron health are thought to be released in very limited quantities so only appropriate neurons or neurons that have arrived at the correct time will be able to access these, they are also dependent on environmental cues and enrichment

glial development

astrocytes and oligodendrocytes are generated after neurogenesis in the developing brain is complete, they are the last to mature so after all neurons are formed, matured and sent their signals, however they continue to form throughout the life of the brain

GFAP

helps identify stem cells too, can mark radial glial cells too

BrdU + BdU

helps identify target cells/dividing ones

neuronal markers

neurofilament (NF-L), neuron specific enolase (NSE) and microtubule associate protein (MAP-2)

neurons

excitable, receive, process and transmit information

microglia

responsible for innate immunity

astrocytes

maintain BBB integrity, participate in synapses,, markers include GFAP and Vimentin

ependymal cells

build barriers between compartments, marked by FOXJ1 expression

oligodendrocytes

produce myelin sheaths

vulnerable post mytotic neurons

in Go they stay in the post mitotic stage and stay there for life so there’s a finite number of neurons, axon mitochondrial clusters are really useful for long distance transport of different substances where they either become perinuclear mitochondria for biogenesis or they become synaptic mitochondria for ATP production

chemoattractant

can help move different types of adult stem cells into lesioned/damaged areas

key process of cellular and molecular basis of aging

accumulation of DNA damage and reduced repair efficiency, mitochondrial dysfunction leading to reduced ATP production and increased ROS generation, chronic low-grade inflammation (neuronal cells are very vulnerable to this), and its impact on neural cells, there is also cellular senescence and altered intercellular communication during aging, you need lots of ATP in neurons to reestablish the concentration gradient + maintain it

neuronal impact of aging

increased vulnerability to oxidative stress and apoptosis

glial cell impact of aging

dysregulated support functions, enhanced pro-inflammatory signaling, switches from being helpful to being inhibiting

brain atrophy

widespread reduction in brain volume so that includes sulci + gyri becoming more prominent, especially in the prefrontal cortex and HPC, grey matter thinning and loss of cortical neurons (migrating ones)

white matter degeneration

reduced integrity of myelin sheaths, leading to slower signal conduction, increased white matter hyperintensities visible on MRI

hippocampal shrinkage

impact on memory and learning processes, reduced neurogenesis in the dentate gyrus

dopamine decline via neuronal age

reduction in the nigrostratial pathway, affecting motor control and reward processing

serotonin decline via neuronal aging

decreased levels linked to mood disorders and reduced emotional regulation

acetylcholine decline via neuronal aging

diminished function in cholinergic neurons, impacting memory and attention

receptors changes w/neuronal aging

downregulation and desensitization of neurotransmitter receptors, altered receptor binding in aged brains

mitochondrial function

supports rapid cell growth and synaptogenesis, ageing results in mitochondrial dysfunction, reduced ATP production and increased oxidative stress, its linked to neurodegeneration cause its a hallmark of diseases like Parkinson’s and Alzheimer’s

protein homeostasis/proteostasis

mechanisms ensure proper protein folding and degradation during early development, ageing disrupts these mechanisms leading to protein aggregation, aggregated proteins like amyloid beta and tau are toxic in alzheimer’s and parkinson’s, when proteostasis collapses apoptosis is inefficient so get aggregation and misfolded proteins

neuroinflammation

microglia regulate synapse formation and debris clearance during development (constant surveillance), aging primes microglia for chronic neuroinflammation, brain has all inflammation factors + no where to go, see this in neurodegenerative disorders, persistent inflammation accelerates neuronal damage, seen in AD and Huntington’s

epigenetics and DNA damage

epigenetic modifications regulate gene expression during brain development, ageing increases DNA damage and dysregulates epigenetic controls, DNA repair mutations and epigenetic changes contribute to neurodegenerative diseases, repair mechanisms not functioning as well

calcium homeostasis

Ca2+ signaling is essential for synaptic activity and neuronal function in development, dysregulation of Ca2+ homeostasis in ageing leads to excitotoxicity, excess Ca2+ influx contributes to neuronal death via apoptosis in AD and motoneurons in ALS