next lecture: induction/signaling requirements of inducer and responder cells cascades of inductive...
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Next lecture: Induction/Signaling
• Requirements of inducer and responder cells
• Cascades of inductive events are involved in forming organs
• Examples of the kinds of cell communication
• Important signaling pathways in development– Notch, TGF, SHH, Wnt, FGF
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“Official glossary” from Wolpert
• Induction: The process whereby one group of cells signals to another group of cells in the embryo and so affects their development
• Competence: The ability of a tissue to respond to an inducing signal. Embryonic tissues remain competent for a limited time (Can depend on prior inductive events)
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Competence factors
• Not all tissues are able to respond to the same signals. Competence is actively acquired– Receptors, signaling molecule– Transcription factors (chromatin state)
• Competence factors are specifically required in the responding tissue, not the inducer– Demonstrated in recombination experiments
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Recombination experiments: First name the players…(fig 6.1 from Gilbert)
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Then play…Fig 6.3 Gilbert
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Cascades of inductive events form the organ: Reciprocal induction
Of Gilbert
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Two kinds of induction (plus one)
• Instructive interaction: A signal or factor which tells the developing cell what it is
• Permissive interaction: A signal or factor that allows the cell to become what it is
• Selective interaction. A factor allows the cell to be “selected” into one lineage or another after a stochastic (random) change
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For example, CD4 vs. CD8 T cellsSelection vs. Instruction
TCR-I
TCR-II
CD8
CD4
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Juxtacrine interactions
• Involve cell surface receptors on inducer and responding cells (no soluble factors)
• Cell death/apoptosis pathways– Fas (CD95)/FasL
• Notch/delta pathway– Involved in many binary cell fate decisions– Examples in flies, worms and mice
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Cell death pathwaysFigure 6.27 of Gilbert
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Notch is involved in a wide array of binary cell fate decisions
• C. elegans:Ventral uterine vs. Anchor cell and vulval development
• Drosophila: Neural vs. Epidermal cells
• Mouse: Embryonic lethal, Demonstrated affects in the immune system and others
• Human: Notch deficiencies cause birth defects
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Notch/delta pathway(fig 6.29 of Gilbert)
This model is simplistic little evidence for nuclear localization of Notch in developing organisms
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Players in the Notch pathway
• Receptor family: Notch/lin-12, glp-1
• Ligands: (DSL) Delta, Serrate, Lag2, Jagged
• Processing: ADAMs (Kuz, TACE) and Secretases (Sel-12/presenilins)
• Downstream effectors: CBF1, Su(Hairless), Lag1 (Collectively called CSL)
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Proteolytic processing of Notch is
complicated Figure 1 from Weinmaster (2000)Curr. Opin. Genet. Dev. 10:363-369
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Presenilins
• Multipass transmembrane proteins
• Mutated in inherited, early onset Alzheimer's disease
• Involved in cleavage of amyloid precursor protein (APP)
• Evidence that they are proteases or co-factors of a protease
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Evidence linking presenilins with Notch signaling
• Homology between PS1 and Sel-12 of C.elegans (sel-12 facilitates Notch signaling)
• PS and Notch deficient animals have similar phenotypes (Drosophila and mice)
• PS is required for access of Notch to the nucleus and, thus, Notch signaling
• Defects can be rescued by providing exogenous PS
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Current view of Notch signaling Figure 2 from Weinmaster (2000) Curr Opin Genet. Dev. 10:363-369
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Notch involvement in cell fate
• Examples of Notch involvement in inductive interactions (signaling between non-equivalent cells)
• Lateral specification (occurs in a population of equivalent cells)– Involves the amplification of a stochastic small
difference between equivalent cells
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Lateral specification in C. elegansFrom Greenwald (1998) Genes. Dev. 12:1751-62
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Evidence for feedback mechanism in lateral specification
• Constitutive active mutants of lin12 have no AC
• Mutants eliminating lin12 activity have 2 AC
• Mixing experiments between two types above– Lin12 - cells always became AC– Lin12 WT cells always became VU
• Behavior different from WT in non-mosaic situation where these cells have equal chance to become AC or VU
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One way to generate a bias in Notch activity-C. elegans vulval development
From Greenwald (1998) Genes. Dev. 12:1751-62
fate adoption is 2o-1o-2o
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Gilbert Chapter 6 errors
• Lag2 is not secreted but transmembrane. This is the ligand for lin12/Notch (p.169)
• Figure 6.40 on T-lymphocyte signaling: The pathways leading from the receptors are not correct. (Notice, there is no reference)
• Figure 6.19: Details appear to be in dispute
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Paracrine factors and interactions
• Transforming Growth Factor (TGF)-• Sonic Hedgehog
• Wnt
• Fibroblast Growth Factor (FGF)
• Retinoic Acid (RA)
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TGF-
• Over 30 members of the TGF- family
• Subfamilies, TGF, Activin, BMP, Vg1
• Processed proteolytically with the C-terminal region conatining the mature peptide
• TGF peptides can homo- or hetero-dimerize
• TGF signal transduction involves multiple receptors which activate cytoplasmic “Smads”
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Smad pathway (fig 6.20) p.159
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Division of labor among SmadsCourtesy of J.F. Doody (J. Massague lab @MSKCC)
Smad 6 and 7 are inhibitory proteins induced by antagonists of the TGF signaling pathway, such as -interferon (Smad7)
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The Smad familyFrom Piek, et. al. (1999) FASEB J. 13:2105-2124
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A more complete TGF pathway From Piek, et. al. (1999) FASEB J. 13:2105-2124
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Evidence for non-redundant TGF family involvement in development (due to expression patterns)
• TGF-1 knockout mice have defects in blood and vasculature (many die prenatally)
• TGF-2 knockout mice have multiple organ malformation (perinatal death)
• TGF-3 knockout mice die shortly after birth due to defects in pulmonary development
• Information from Piek, et. al. (1999) FASEB J.
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Next lecture: Induction/Signaling
• Requirements of inducer and responder cells
• Cascades of inductive events are involved in forming organs
• Examples of the kinds of cell communication
• Important signaling pathways in development– Notch, TGF, SHH, Wnt, FGF