Signaling Pathways and Development Flashcards
Hh and Wnt pathway facts
signally is involve din maintaining stem cell niches in various tissues
-imlicated in cancer and tissue repair
-important for dev
occurs in primary cilium and gets sent down the ciliary shaft
uses of indian, soncc, desert hh
dev of bone and cartilage
dev of CNS
dev of peripheral nerves
Hh (or any hh variant)
ligand
secreted hydrohphobic proteins that are produced/secreted by localized cell group which they diffuse away from
Ptc receptor
Patched
binds hh ligands
-12transmembrane protein with homology to actuarial proton driven transmembrane transporters
Smo
Smoothened-no bind Hh ligands-interacts with pt.
-7 alpha hlix g protein coupled transmembrane protein
enter primary cilia
gli/ci proteins
gli rep/act
how turned on/off
tfs that either activate or rerpesses hh genes
rep=partially proteolyses protein that functions as transcriptional repressor-represses hh gene
act-full length protein that functions as a transcriptional activator-activates hh gene
phosphorylated to turn off-results in targeting to proteasome after recruit another complex
-alot of phosphorylation
remove phosphates to send to nuc
pka
protein kinase a
phosphorylates gli/ci proteins to target them for prteolysis in proteosome
regulation of gli/ci protein proteolysis
when smo is activated by ptch- dephosphorylate and activate gli-goes into nucleus
when smo not activated by pitch-gli is phosphorylated and sent to proteasome
primary cilla
nonmotile cilia that exist on most cells of vertebrate body
sense ECM info
Role of cilia in human function
invovled in hh signalling
localize signal transduction componentes
cilipathies result in vision, hearing, smell. situs inverses, hh signaling, etc
IFT proteins
intra flagellar transport
moe cargo along microtubules
maintain iila integrity
link with dynenin=allow movement up and down cilia
how use IFT protein for Glirep and GLIact
Rep-PTC inhibits Smo translocation into cilium, IFT proteins shuttle GLIrep into nucleus
Shh blocks pt. allow smooth to translocate into cilium-IFT proteins shuttle glitch into nucleus
Congeinital human Hh disorders affect which body parts
limba nd CNS
where is shh localized in early developmoent
limb buds/early CNS as organizing centers
lends to development of polarity
Organizing centers direct
pattern formation
ZPA
what is ZPA morphogen
zone of polarizing activity
proteins made here fuse away
-induce secndary tissue development
Shh
Shh knocout mice
cyclopedia-failture oto problery divide eyes into two vanities
holoprosencepahy-one forebrain-one brain hemisphere
servereCNS and limb defects
replace ZPA with latex bead covered in Hh
Hh protein coated beat micmickes effect of ZPA
how does hh control digit pattern
graded inhibition of glib proteolysis
shh is required to inhibit formation of gli3rep
- no shh gli3 rep on
- yes shh gli3 act on
binary-either gli3 rep on or gli3 act on
gli3rep formation is controlled by graded SHH
what does GLIact do for formation
nothing for digit formation-all about where gliREP is not
what does reduction of glib rep result in
dorsal CNS hypertrohpy
Shh relationship to GliACT and how affects phenotype of CNS
what does gliact induce
basically gli ACT and is not required-just can’t have GliREP
pituity, hypo, sinal chord, etc.-need shh/gliact-having nothing would result in these not forming
what does
ss-/-
shh-/-, gli+/-
gli -/-
shh-/-m gli3 -/-
look like
ss-no brain differentiation/no finger differentiation-brain is almost deleted
shh/gli-dorsal part of brain is overgrown (hand gets messed up
gli-similar to adding another zpa-too much cns creation/too many digits
double knocout-dorsal cns hypertrohic/too many fingers
what happens between difference of reduced shh and enhanced in regards to dentate gyrus
reduced-depletetion of dentate gyrus
increase-increased dentate gyrus granule cells
encepholoy
product of pover production of CNS progenitor cells-link between Hh and stem cell proliferation
holoprosencephaly
dev disorder mainly characterized by incomplete midline formation during forebrain dev
-cyclopedia, single forebrain besiicle, single front tooth
results from shh defecinency (even haplo is enough)
-only in brain face tissues-other tissues are less sensivive?
smoothened and hpe
smoothened is critical drug/toxicologal target
not targeted by shh-targeted downstream
other ligands can turn smo on-neuro defects
what is required for production and secretion of mature shh+ how+what loss of function cholesterol
cholesterol!
Hh is usually large precurosor that is cleaved when added to cholesterol
results in HPE-probably due to lack of dhcr7 gene
Hh disease facts due to increased signalling
possibly result from mutation in negative transduction pathway (keep shh off)
dereased Gli3 repressor actiity (increased Shh/Gli3 act)
Many forms of cancer
Smo inhibitors may have benefits (so shh doesn’t keep firing)
gli 3 diseases +congeniality
all are congenital
mutations lead to loss of gli3rep-three auto dominant dryness
overlord of digits, limb/brain defects
gliblastoma
due to increase of hh signaling
agresseive cns tumor
Medullablastoma
in cerebellum during dev
most common malignant tumor
occurs due to too much hh signaling
- or one ptc allele missing
- ptc inhibits pathway when shh not bound
anything resulting in too much shh pathway results in this
wnt/wingless
where are two intracellular pools of beta catenin
segment polarity gene in flies
cytoplasmic-invovled in signalling-regs target gene expression
cell membrane-involve din cell adhsion/tissue homeostasis-assocaited with caderhines an dadherins junctions
wnt pathway w/ wnt
wnt ligand binds to frz(frizzeeld) and arrow correctors
destruction complex dissocated-interrupts beta catenin phosphorylation
un phosphorylated beta catenin enters nucelus where finds to tcf/lef protein to turn on target gene expression
want pathway w/o b-catenin
tcf/lef proteins associate with groucho/grg to block target gene expression
tcf/lef proteins are bi-functional trx factors
destruction complex + what happens after
axin, APC, Gsk3 phosphorylate beta cattiness when no wnt
beta-catenin-P is substrate for beta TrCP degredation
PP2a
-PP2A removes P form beta catenin
wnt + cancer
simlpy changing beta catinin stability can cause cancer
-can result in constitutive activation-cancer
APC and cancer
linked with collateral cancer-too much beta catenin
what is canonical wnt pathway
regulation of beta cat into the nucleus
what is noncanonical wnt pathway
no beta cattiness or things that effect beta catenin
has tissue polarity function
