Stem Cells & the Developing Brain Flashcards
WHY is stem cell proliferation is essential during development?
→ to understand how neural cell fates are determined
2 key factors to consider in stem cell proliferation
Molecular factors = genes and transcription factors
Cellular factors = position and timing of cell birth
neural cell fates are determined in…
a spatio-temporal manner (i.e., space & time - where and when a cell is born has a large influence on what it becomes)
What is cell fate regulated by?
a number of factors - but ultimately depends on the integration of intrinsic signals which are genetically inherited from precursor cells and extrinsic signals that come from the environment
Neural stem cell potential?
Multipotent - many potentials!
→ can become a neuron, astrocyte and oligodendrocytes
Glial progenitor cell potetnial?
Bipotent - only gives rise to glia (there are only two types! Astrocytes & Oligodendrocytes)
Where does the nervous system derive from
the ectoderm layer
Bone Morphogenetic Proteins?
a key group of developmental signals
Why would we antagonise BMPs?
to induce differentiation of the neural ectoderm, i.e., the blue print of the nervous system
Importance of Neurogenic Vs Gliogenic signals?
to determine whether neural stem cells choose a neuronal or glial fate
Which comes first in development - Neurogenesis or Gliogenesis?
Neurogenesis precedes gliogenesis in development of the NS
Lateral inhibition?
inhibition of the cell lateral to another cell…
NB in the initial stages of development of the NS
What is key to the behavior of neural progenitor cells?
the Neural tube under goes two types of division
- Symmetric division: - two identical daughter cells
- Asymmetric division: - two daughter cells, however only one continues dividing and the other migrates and differentiates into a neuron
Symmetric Division
NB to increase the pool of neural progenitor cells in order to make the required amount of neurons that are needed by birth
Asymmetrical divison
to maintain a stem cell, but also to give rise to a stem cell which will produce neurons
What marks the onset of neurogenesis?
the switch from symmetric division to asymmetric division
What is the Delta/Notch signaling pathway?
Neurogenic genes which inhibit neurogenin gene expression
What are Neurogenins?
a family of proneural genes which drive neuronal differentiation
When neurogenin expression is blocked..
When neurogenin expression is blocked in both cells to an equal extent, they have equal levels of delta and these stem cells will not differentiate and will maintain a stem cell fate (to increase the progenitor cell pool)
What if one cell increases the expression of the delta ligand?
This will result in a greater signaling through the notch receptro in the blockade of neurogenin in the other stem cell, so this means it will maintain a stem cell fate - the cell with a greater expression of delta: switches on expression of other genes required for neuronal diffrentiation
why can’t cells diffretniate at the same time to become a neuron?
Lateral inhibition - involves delta notch inhibition of neurogenesis which is NB in neuronal differentiation.
- When this process is unbalanced, one of them will undergo neuronal differentiation (asymmetrical)
Most proneural genes encode..
basic helix-look-helix transcription factors
→ loss of proneural gene expression = decreased neuronal production etc
Why is cell division so important in the neural tube?
for populating the developing nervous system with enough cells to ultimately generate the required number for what is needed for normal development
asymmetric division is NB because..
not only does it allow the development of neurons, it also allows us to keep the progenitor cell pool intact
Zika Virus
infects the proliferating neuronal epithelial stem cells, causing hypo morphism of brain development (smaller brains) because Zika virus kills these developing progenitor cells, meaning there isnt enough of them to make neurons needed for development
Nestin
intermediate filament expressed by neuro epithelial stem cells
Brain lipid bring protein (BLBP)
Cells which are Nestin positive & BLBP negative - they are undergoing symmetric division
Use of these markers very useful in identifying this process
Describe mitotic spindle during asymmetric division
Parent cell attaches to apical complex. NPCs sit on the luminal surface, the spindle is horizontal to the luminal surface & provides cell division in which only one cell maintains contact with this surface. The other cell loses this contact and migrates out into the developing brain, starting neuronal differentiation
Mitotic spindle during symmetric division
Vertical to the luminal surface
Apical complex
Expresses Par3 protein - proteins in the apical complex (Par complex) at the apical pole of the cells activate delta notch signaling
The basal complex
Consists of proteins NB for promoting neuronal differentiation (Ccnd2, Trim32)
What is neural patterning?
the process through which cells in the developing nervous system acquire distinct identities according to their specific spatial position
The area where neuronal patterning is most extensively studied
The spinal cord
- accesible
- small region in cross section
- the cellular architecture of the spinal cord is known very well
Morphogens
e.g., Shh & BMP
a secreted signalling molecule; that elicits different cellular responses depending on its concentration
What is a major determinant of neuronal cell fate in the spinal cord?
dorsal-ventral positioning
2 signalling centres at the ventral and dorsal midline
- dorsal roof plate
- ventral floor plate
What does the dorsal roof plate secrete?
BMPs (bone morphogenetic proteins)
What does the ventral floor plate secrete?
Sonic hedgehog (Shh)
The absolute concentration of the __ acting on any one cell determines developmental fate
morphogen (e.g. BMP, Shh)
Does ventral patterning play a role in motor or sensory spinal circuitry?
Motor
Does dorsal patterning play a role in motor or sensory spinal circuitry?
sensory
Motor neuron progenitors express…
Nkx6.1 and Olig2
Neuron progenitors in other ventral domains become …
Interneurons
Nkx6.1 turns on expression of?
Olig2 (bHLH TF)
Wnt ligands bind to
Frizzled receptors and co-receptors LRP5/6
Mature BMP dimers exert their effects by binding to __, leading to…
BMPRs, leading to recruitment and phosphorylation of receptor-regulated Smad proteins (Smad-1/5), which then complex with Smad-4 and translocate to nucleus
Neuron differentiation of Class __ interneurons is BMP/Wnt signalling-dependent
54
The patterning of dorsal spinal cord interneurons requires __ signalling
BMP-Smad signalling
Neurogenesis has mainly been studied in the __, whereas neural patterning has mainly been studied in the __
Cortex
Spinal Cord
