Development first lecture Flashcards
Describe fate, specified and determined in the context of stem cell development
Fate describes what groups of cells will normally develop info
Specified is when a group of cells can be isolated and cultured in a neutral environment and develop into their normal fate
Determined is when a group of cells still develop into their normal fate when transferred to a different region of the embryo, ie. They are immune to other influences in the new location
How are cells determined?
A result of induction
Result of synchronised changes that occur through interaction between two or more cells with distinct cell histories
Need the correct induction and competent receiver
Describe other types of inductive events
Epithelial-mesenchymal interaction
Epithelial are sheets or tubes of connected cells
Mesenchymal are loosely packed unconnected cells
Involved in the induction of cutaneous structures
Eg. Chick epidermis secretes a protein to the underlying dermal cells to form condensations ➡️ the dermal condensations turn the signal back to form epidermal structures that form over the condensed mesenchyme
What mediates induction?
Paracrine diffuse signal to many neighbouring cells
Juxtacrine relies on direct physical communication so can only contact immediate neighbours
Describe the importance of notch in drosophila
Dominant mutation where the loss of one copy leads to notching of adult wings
Loss of both copies is embryonic lethal because loss of notch leads to hypertrophy of the nervous system
Loss of notch triggers over-production of sensory bristles in the adult and failure To maintain appropriate spacing
Describe notch
Notch is a cell surface protein
Interacts with either delta or serrate in fruit fly or delta-like 1,3,4 and jagged1 in humans
Notch binding requires EGF repeat 11 and 12
Describe the concept of the epigenetic landscape
As development progresses organisational complexity increases
Cell fate is referred to as stably conferred
How does notch signalling activate transcription?
Notch is cleaved upon binding of ligands
To liberate the notch intracellular domain (ICD) two sequential proteolytic events occur
1. Cleaved in the extracellular domain by TACE
2. Cleaved in the transmembrane domain by gamma-secretase
Once the notch intracellular domain is liberated by cleavage it is trafficked to the nucleus and binds to the transcription factor CSL which is bound to the repressor protein NCoR
ICD binding to CSL displaces co repressors and recruits transcription co-activators to activate transcription
What are the targets of notch signalling in humans?
Hairy enhancer of split family of genes (HES)
They are basic helix-loop-helix transcription factors
Summarise the result of notch activations
Notch engagement➡️ICD liberation➡️CSL switched to activate transcription➡️HES gene transcription➡️ represses developmental regulators
Describe lateral inhibition by notch
Delta expressed on one cell interacts with the notch expressed on a neighbouring cell activating the notch pathway, eventually repressing notch
Neighbouring cells are engaged in competitive interaction
Slight differences in delta expression are amplified and one cell ‘wins’ activating the notch pathway in neighbouring cells repressing proneural genes
Describe Fringes role in boundary formation in the wing of the drosophila
Notch can be glycosylated in the ER of the cells express glycosyltransferase enzyme
Glycosylation of the notch ECF domains affects interaction with ligands
BLOCKS serrate
ENHANCES delta
Fringe catalyses the addition of the second of four sugar groups
Fringe is expressed in the dorsal compartment of the wing with serrate
Delta is expressed in the central compartment of the wing
Fringe restricts delta binding to the boundary of the dorsal and central surfaces allowing the wing margin to form
Describe an example of boundaries mediated my notch in mammals
The boundaries between somites
Gene targets in the notch signalling pathway eg. hes1, hes7 and lunatic fringe are expressed in an oscillating pattern within the pre-somitic mesoderm, sweeping anteriorly
As more anterior cells express hes1/7 less caudal cells do so the wave of expression narrows as it moves up the PSM until only a small band of cells email that mark the future posterior region of the somite
Describe the clock and waveform model
The primitive node is a source of a morphogen Fgf8 that inhibits somite formation in he PSM
As the node regresses the more anterior cells escape this inhibition
When coupled with oscillating activation of the notch pathway and hes1/7 expression the regression of the primitive node allows the regular progressive addition of pairs of somites
