Tissue Repair Flashcards
What are the sources of signals in the developing mammalian midbrain?
Notochord (Shh)
Isthmic organiser (Fgf8)
Which structures are at the dorso and ventral ends of the developing brain respectively?
Dorso: Roof plate
Ventral: Floor plate
Which end are the motor neurons at?
Ventral: by the floor plate
Where is Shh secreted in the midbrain?
By the floor plate and notochord, results in a gradient across the dorso ventral axis
How does the Shh signalling pathway work in the midbrain cells?
-Shh binds to Ptch1 in the membrane and pulls it out the way
-This causes SMO to move in ti that spot in the membrane
-This has the effect of changing GLI from an inhibitor to an activator and causes target genes translation
How are the genes activated by Shh changed for different cell types?
The high-low concentration gradient. Also affects the strength of activation
At what concentration of Shh is GLI activated?
High
Where do dopaminergic neurons form?
Close to the floor plate
What gene product is required for dopamine synthesis in DA neurons?
Tyrosine Hydroxylase
What genes are expressed in floor plate progenitors and DA neurons which have left the floor plate?
Msx1/2 : FP progenitors
Nurr1 : DA neurons
Lmx1a : Both
How can low threshold activated gene products be excluded from certain cell types?
Inhibitors
Which part of the brain is tyrosine hydroxylase activated in?
Midbrain
What is the definition of an organiser?
A group of cells which transmit signals to influence the developmental fate of nearby cells (paracrine signalling?)
What are the morphogen gradients present in the midbrain development?
Anterior-Posterior Low-High Wnt
Dorso-Ventral Low-High Shh
Anterior-Posterior Fgf8 produced from isthmic organiser below the midbrain
Which morphogen does the Isthmic organiser produce?
Fgf8
What do the different brain development morphogen signals instruct?
High Shh instructs Ventral tissue
Fgf8+Medium Wnt instructs midbrain tissue
Fgf8+High Wnt signalling instructs Hindbrain tissue
What causes Parkinson’s?
Dying back of DA neurons
What part of the brain are the dopamine terminals located?
The Striatum, split into the Caudate and Putamen
What is a method of reintroducing DA neurons?
Transplantation of stem cell derived tissue
Where is the pigment Neuromelanin located?
The Substantia Nigra
What are the possible issues with using foetal embryonic stem cell tissue?
Ethical issues
Poor and unpredictable supply of tissue
Poor quality and heterogeneity of tissue
What can be used as a source of stem cells?
Embryonic stem cells from blastocysts
Induced pluripotent stem cells from adult blood or skin cells (iPSCs)
How are pluripotent stem cells induced to differentiate into Midbrain tissue?
Dual Smad inhibition to inhibit BMP and Activin/TGFbeta signalling pathways
Induced differentiation with appropriate factors (eg Shh)
In what state can stem cell derived tissue be transplanted into the brain?
DA neuron progenitor can be transplanted. Not fully differentiated ones
What is the process for making Midbrain floor plate tissue in vitro?
-Dual Smad inhibition, produces anterior ventral tissue
-High Shh activation, produces Ventral tissue
-Medium Wnt signal, Caudal tissue
-Timed Fgf8b signal, produces Midbrain tissue
Where are the DA neuron cell bodies located in the striatum?
The core
How do the implanted DA neurons avoid innervating the cortex?
They partner with their natural partner neurons which are only present in tissues that they should be innervating.
