Ways of cell signalling.
1. Paracrine factors (diffusable signals) - can act over long distances. 2. signals deposited into extracellular matrix (ECM) - can be long lasting 3. Contact (cell-cell adhesion molecules, gap junctions - high spatial precision.
What has the invariable cell lineage and fate map of c. elegans revealed?
Programmed cell deth - apoptosis - analysed. genes involved identified.
What are the apoptosis genes?
Caspases in crucial for apoptosis. - they cleave a number of cellular proteins and bring about cell death. Regulated by a number of homologous genes - EGL-1, CED-9, CED-4.
What are the genes which control timing of development processes (discovered in C. Elegans)
heterochronic genes, e.g. lin-14, loss of function mutant causes stage 1 of development to be skipped. or lin - 4 and Lin-14 gain of func causes repetition of L1 pattern.
What is the Lin-4 / Lin-14 relationship?
Lin-14 is repressed by Lin-4 through mi-RNA mi-RNA as regulator of expression very common in eukaryotic kingdom
What are si-RNA?
Short interfering RNA deactivates mRNA by cleaving.
What is mi-RNA?
micro RNA deactivates expression by binding to a target mRNA (usually in the 3' untranslated region) or degrates the bound target mRNNA
What control mechanism are responsible for the invariable cell fate of C. Elegans?
Both mosaic-type control and regulation control.
mosaic type: P granules are asymmetrically segregated during the first four cleavage divisions. P granule segregation correlates with germ cell fate. Laser ablation of P4 led to the production of larvae with no germ line. At least one known component of P
granules (PGL-1) is required for germ cell development. P granules function as germ line fate determinants.
The par genes (par: partition, par 1-6) are required for asymmetric segregation of the P granules during the early cleavage divisions. Homologous genes are also involved in establishment and maintenance of cell polarity in other metazoans.
regulative type: ABa versus ABp development
What are the two theories of development from the 1800, and the experiments which supported them?
Weismann's theory of nuclear determinants (mosaic) supported by Roux Regulative Driesch - complete organism still grows despite ablation of cells in early stage.
What is an example of regulative development in C. elegans?
The induction of ABp identity by P2 P2 expresses GLP-1 (Notch homologous). Both ABa and ABp have APX-1 receptors (Delta family). When ABp is killed, ABa is adjacent to P2. and takes on the identity of ABp
Overview of C. elegans vulva development
1. creation of the vulva equivalence group (six cells P3p, P4p,....P8p 2. induction and lateral inhibition: specification of primary, secondary and tertiary cells. 3. Cell proliferation 4. Morphogenesis
Which cells in C. elegans vulva development are primary, secondary and tertiary?
Primary: P6p Secondary: P5p and P7p Tertiary: Pep, P4p and P8p (these have a non-vulva fate)
What cell is responsible for determining the fate of the C. elegans vulva cells?
What is the signalling pathway which generates the vulva in C. elegans?
1. Lin-3 signal from anchor cell induces P6p to adopt the primary fate.
2. lateral signal from P6p is received by Lin-12/Notch receptor in neighbouring cells. Inhibits them from adopting primary fate. 3. a consecutive signal from the epidermis also represses development into the primary fate, but is overruled by the signal form the anchor cell.
What does the Drosophila eye comprise of?
What does each ommatidia comprise of?
8 photorecepor cells (R1-8) Cone cells secrete the lense Pigment cells provide optical isolation.
Overview of eye development.
1. morphogenitic furrow (MF) moves from p to a across the imaginal disc. Single cells are selected in the MF as R8 precursor cells (lateral inhibition involving Notch)
How are the cells in the eye determined.
1. R8 signals with Spitz->Torpedo to iduce two R2,5 cells 2. R8,2,5 signal with Spitz->Torpedo R1,3,4,6 3. R1,3,4,6 signal with Spitz->Torpedo to induce cone cells. 4. cone cells signal with Spitz->Torpedo to induce pigment cells 5. R8 signals with Boss>Sevenless to induce a single contacting cell to develop as R7 This is an RTK signalling path
Are RTK signals selective or instructive?
They must be selective because exactly the same pathway can produce a differnt outcome.
How can an RTK signal lead to different changes to different cells?
The effect of the signal depends on a cells developmental history and its current state of gene expression.
cell death and human health
Aberrations in programmed cell death processes are part of the etiology and/or pathology of many diseases.
- inappropriate inactivation of the death program (cancer, autoimmune diseases, …)
- inappropriate activation of the death program (chronic neurodegenerative diseases, stroke, myocardial heart infarction, …)
Not all cell death occurs via apoptosis (execution via caspases)
- autophagy (self digestions in specialized lysosomes)
- necrosis (cell lysis)
- Wallerian degeneration (after nerve cut)
- various other non-apoptotic cell deaths (plasmid addiction, etc.)
Not all cell death is programmed. While apoptosis with all its characteristic features does not occur in plants, it is very clear that programmed cell death (involving distinct mechanisms) does also occur in plants.
genes which control the timing of developmental processes
different ways of cell fate diversification
1. asymmetric egregation of fate determinants. e. g. - germ line determination in C.ele. and D. mel. - stem cell renewal in D. mel. neuroblasts
2. lateral inhibition, cell induciton. e.g. - germ line determination in mouse and humans - stem cell renewal in D. mel. ovary - vulva development in C. ele. and eye development in D. mel. are important examples because their analysis allowed for crucial breakthrough towards a molecular understanding of cell-cell interactions in development.
induction of VPC fate by a signal from the AC cell: a conserved signaling pathway
RTK pathway (receptor tyrosine kinase)
ligand receptor sets off cascate inside cell which modulates transcription
D. melanogaster Torpedo is homologous to C. elegans LET-23 and mammalian EGF receptor. D. melanogaster Sevenless belongs also to the receptor tyrosine kinase family like Torpedo, LET-23 and the mammalian EGF receptor. Signaling downstream of the activation of all these RTKs involves the same ras/MAP kinase pathway.