PHYSL 371: gliogenesis, neurogenesis, and organoids

why is neurodevelopment important

it helps us understand how the brain is built and the basis to understanding neurodevelopmental disorders

what does it mean when a cell has high potency

had the potential to become different cell types

when cell has the greatest level of potency

an initailly fertilized egg (zygote) which has the potential to differentiate into any cell type

what happens to potency of new cells as development moves in one direction to generate specific cell types

the potency of the new specific cell decreases

what underlies specificity of cells

a change in transcription (gene expression)

how is gene expression measured

by single cell transcriptomics

How are cell types determined?

one type of cell is defined as transcriptionally similar cells (cells with similar active genes will be classified as a cell type)

how does a cell receive its adult cell type identity

a gene regulatory network which determines gene expression

what is the gene regulatory network instructed by

signals or cues in the environment of the cell

what do environmental cues do

instruct transcription factors to engage and to act on promotors and enhancers which will lead to a reaction of the cell to the environmental signals

cell proliferation

process where a cell grows, divides, and produces two identical daughter cells which leads to an exponential increase in cell numbers

Cell Differentiation

process by which unspecified stem cells mature into specialized cells with distinct structures and functions (such as nerve or muscle cells)

morphogenesis

the biological process that causes a cell, tissue, or organism to develop its shape

programmed cell death

process by which a cell dies usually to benefit an organism (ex. formation of fingers is a result of apoptosis)

what is the first structure a zygote turns into

a blastocyst with an inner cell mass (around day 5-6)

where does the blastocyst go

it implants into the uterine wall and becomes an embryo

what 3 layers does the blastocyst separate into after implantation in the uterine wall

ectoderm, mesoderm, and endoderm

what does the ectoderm develop into

the outer layer of skin (epidermis), hair, nails, and the entire nervous system (brain spinal cord, and nerves)

what does the mesoderm develop into

the musculoskeletal system (bones, muscle, connective tissue), circulatory system, heart, kidneys, and internal sex organs

what does the endoderm develop into

the linings of the GIT and respiratory system, the liver, pancreas, lungs, thyroid, and bladder

neural plate formation

the ectoderm (outer layer) differentiates to form a flat, ribbon-like structure called the neural plate (16 days)

neural folds

A pair of ridges all along the edge of the Neural Plate that begin to curl towards each other

neural groove formation

the edges of the neural plate lift up to form neural folds while the center dips down to create the U-shaped neural groove

neural tube closure

the neural folds move toward the midline of an embryo and fuse which transforms the neural groove into the hollow neural tube

neuropores

Openings at the anterior and posterior ends of the neural tube

neuropore closure

the neuropores are last to close, 25 days for anterior and 28 for posterior

what is the precursor to the entire spinal cord

the neural tube

what portion of the neural tube expands to form the brain

the anterior (head) portion of the neural tube

what does the rest of the neural tube develop into

the spinal cord

what signalling molecule is found in high concentrations on the dorsal side of the neural tube

BMP

what signalling molecule is found in high concentrations on the ventral side of the neural tube

SHH (sonic hedgehog)

neural crest cells

cells at the junction of the neural plate at epidermis which migrate away and become important precursors for various cell types throughout the body including peripheral nerves and other tissues

paracrine signalling

local cellular communication where a cell releases signalling molecules (ligands) that diffuse a short distance through the extracellular space to bind to and activate target cells in the immediate vicinity

what's an example of paracrine signalling

Sonic Hedgehog (SHH) Bone Morphogenetic Protein (BMP) which pattern the dorsal ventral axis

Bone Morphogenetic Protein (BMP)

paracrine signal is responsible for dorsal or roof plate patterning

Sonic Hedgehog (SHH)

paracrine signal that is responsible for ventral or floor plate patterning

juxtacrine signalling

direct form of cell-to-cell communication in multicellular organisms where a ligand on one cell surface interacted with a receptor on an adjacent cell surface (not related)

what is juxtracine signalling used for

controlling the balance between neural stem cell self-renewal and differentiation into neurons

example of juxtacrine signalling

notch-delta signalling

what are the 4 signalling molecules involved in paracrine signalling in the neural cord

BMP, SHH, WNT, and Noggin

what is the paracrine signal that is responsible for rostral patterning

WNT

what is the paracrine signal that is responsible for caudal patterning

Noggin

what are the 3 major subdivisions of the brain in an embryo

prosencephalon, mesencephalon, and the rhombencephalon

prosencephalon

forebrain

what does the prosencephalon differentiate into

telencephalon and diencephalon

what does the telencephalon differentiate into

cerebrum (largest part of the human brain)

what is the cerebrum composed of

the cerebral cortex, basal ganglia and hippocampus

what does the diencephalon differentiate into

thalamus, hypothalamus, epithalamus, pretectum, and gives rise to the neural part of the retina (optic vesicle)

thalamus

processes sensory info before sending it to the cortex

hypothalamus

controls various bodily functions

mesencephalon

midbrain

what is the midbrain responsible for

relaying sensory and motor info and regulating conciousness

rhombencephalon

hindbrain

what does the rhombencephalon differentiate into

metencephalon and myelencephalon

what does the metencephalon differentiate into

pons and cerebellum

pons

A brain structure that relays information from the cerebellum to the rest of the brain

cerebellum

responsible for coordinating movements, posture, and balance

what does the myelencephalon differentiate into

medulla oblongata

medulla oblongata

controls autonomic functions like breathing, HR, and digestion

radial unit (asymmetric neurogenesis) hypothesis for human cortical development

the formation of radial columns of neurons originating from a common progenitor (radial glia) in the ventricular zone (VZ) which moves up to the pial surface. Neurons migrate along the radial glial scaffold, forming these columnar units, which collectively determine the cortex's size and organization (Pasko Rakic and Arnold Kreigstein)

intermediate progenitor (symmetric neurogenesis) hypothesis for human cortical development

radial glial cells (RGCs) can produce intermediate progenitor cells (IPCs) which then migrate to the subventricular zone (SVZ) to undergo symmetric divisions, amplifying the rate of neuron production and contributing to the expansion of the cerebral cortex

symmetric progenitor divisions

radioglia will remain in the ventricular zone and replicate to produce 2 identical daughter cells which increases the pool of radioglia that will eventually differentiate into neurons

notch delta signaling

protein numb present in neuronal cells will cause a down-regulation of notch and up-regulation of delta in the neuron but will cause a down-regulation of delta and up-regulation of notch in the nearby cell by the delta and notch receptor system

what happens to cells with up regulation of notch signalling

they are radioglia that continue to proliferate

what happens to cells with down regulation of notch signalling

they become neurons

what theory does notch delta signalling support

radial unit (asymmetric neurogenesis) hypothesis as it provides an explanation for how cells can divide asymmetrically depending on the signalling they receive

cortical expansion

the significant increase in the surface area of the cerebral cortex (outer layer of the brain) responsible for higher level cognitive functions. This process involves tangential growth of the cortical surface and is closely associated with the proliferation of neural progenitors, development of neruons, and formation of synapses.

what differentiates mice from human cortices

humans have an outer subventrical zone (OSVZ) and and inner subventrical zone (ISVZ) while mice only have the inner

outer subventricular zone (OSVZ)

a specialized germinal zone found in the developing brain of primates and other species with complex cortical structures which generates neuronal cortical expansion seen in mammals

how does cortical expansion occur

in an inside out fashion where the bottom layers are developed first and then work their way up

transient circuits

neuronal circuits that exist only transiently (for a short period of time) during development

example of transient circuits

subplate

the subplate (Sp)

a transient layer in the developing mammalian neocortex that contains early-born neurons and axons that are essential for cortical circuit formation. These subplate neurons guide migrating neurons, establish early sensory pathways, and influence cortical neuroplasticity

what happens once neurons are in the cortical plate

connections between projection neurons are formed, connections with interneurons are formed, axonal inputs (thalamic input), cell type specification, neuromodulators, immune cells, glia cells

what are the 2 major types of neurons in the cerebral cortex

projection neurons and interneurons

projection neurons

excitatory neurons (often pyramidal)

interneurons

inhibitory neurons (mainly GABAergic) but are excitatory during early development and come in 5 major cell types that develop in a sequence

where do interneurons migrate towards

up towards pyramidal neurons in the neocortex to form inhibitory connections

induced pluripotent stem cells (iPS cells)

Multipotent or pluripotent animal stem cells produced from differentiated cells in vitro by the addition of several genes that are expressed which can differentiate into the ectoderm, mesoderm, and endoderm

organiods

miniature, three-dimensional, self-organized cell cultures that mimic the structure, organization, and some functions of real human organs that are derived from stem cells

tonotopic maps

link specific places within the brain to the types of auditory stimuli processed

cochlea

transforms sound waves into electrical signals in the acoustic nerve fibers with high acuity

how does the transformation of sound happen

occurs via vibrating anisotropic membranes (basilar and tectorial membranes) and frequency-specific hair cell receptors

how are frequencies mapped on a cochlea

low frequency specific hair cells are positioned apically (the end) and high frequency specific hair cells are positioned at the cochlear base (the start)

how do RGC axons in the eye know where to go

guidance cues

repellant guidance ques in the optic chiasm

repels filopodia of axons away from the gradient coming from the chaism (does not cross)

attractant guidance ques in the optic chiasm

attracts filopodia of axons towards the gradient coming from the chaism (does cross)

the Hebb rule

when an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth or metabolic change takes place in one or both the cells such that A's efficiency (in firing B) is increases

Cells that fire together, wire together

what modulates branching dynamics and axon growth in nuerons

neuronal firing and correlation

asynchronous stimulation

visual stimulation enhances arbor growth with many new dynamic branches added

synchronized stimulation

visual stimulation of inputs stabilizes the arbor and decreases branch additions

axon guidance

the process that determines the correct series of decisions that guides and axon to its correct destination (target)

neural guidance gradients

chemical cues that growing nerve cells in axons follow during development to correctly wire the nervous system. Neurons detect these gradients by sensing a concentration difference across their growth cone which then triggers a signal to move up or down the gradient by either changing growth rate or turning.

example of neural guidance gradients

netrin, concentration difference of molecules that exert attractive or repulsive forces on the axons growth cone

activity dependent circuit formation

a biological process where electrical activity of neurons shapes and refines the connections, or synapses, between them, leading to functional neural networks where "active" connections become strengthened to form a circuit and eliminating synapses that fire out of sync