Signaling Pathways and Development

Question 1

Hh and Wnt pathway facts

Answer 1

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

Question 2

uses of indian, soncc, desert hh

Answer 2

dev of bone and cartilage

dev of CNS

dev of peripheral nerves

Question 3

Hh (or any hh variant)

Answer 3

ligand

secreted hydrohphobic proteins that are produced/secreted by localized cell group which they diffuse away from

Question 4

Ptc receptor

Answer 4

Patched

binds hh ligands
-12transmembrane protein with homology to actuarial proton driven transmembrane transporters

Question 5

Smo

Answer 5

Smoothened-no bind Hh ligands-interacts with pt.

-7 alpha hlix g protein coupled transmembrane protein

enter primary cilia

Question 6

gli/ci proteins

gli rep/act

how turned on/off

Answer 6

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

Question 7

pka

Answer 7

protein kinase a

phosphorylates gli/ci proteins to target them for prteolysis in proteosome

Question 8

regulation of gli/ci protein proteolysis

Answer 8

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

Question 9

primary cilla

Answer 9

nonmotile cilia that exist on most cells of vertebrate body

sense ECM info

Question 10

Role of cilia in human function

Answer 10

invovled in hh signalling

localize signal transduction componentes

cilipathies result in vision, hearing, smell. situs inverses, hh signaling, etc

Question 11

IFT proteins

Answer 11

intra flagellar transport

moe cargo along microtubules

maintain iila integrity

link with dynenin=allow movement up and down cilia

Question 12

how use IFT protein for Glirep and GLIact

Answer 12

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

Question 13

Congeinital human Hh disorders affect which body parts

Answer 13

limba nd CNS

Question 14

where is shh localized in early developmoent

Answer 14

limb buds/early CNS as organizing centers

lends to development of polarity

Question 15

Organizing centers direct

Answer 15

pattern formation

Question 16

ZPA

what is ZPA morphogen

Answer 16

zone of polarizing activity

proteins made here fuse away
-induce secndary tissue development

Shh

Question 17

Shh knocout mice

Answer 17

cyclopedia-failture oto problery divide eyes into two vanities

holoprosencepahy-one forebrain-one brain hemisphere

servereCNS and limb defects

Question 18

replace ZPA with latex bead covered in Hh

Answer 18

Hh protein coated beat micmickes effect of ZPA

Question 19

how does hh control digit pattern

Answer 19

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

Question 20

what does GLIact do for formation

Answer 20

nothing for digit formation-all about where gliREP is not

Question 21

what does reduction of glib rep result in

Answer 21

dorsal CNS hypertrohpy

Question 22

Shh relationship to GliACT and how affects phenotype of CNS

what does gliact induce

Answer 22

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

Question 23

what does

ss-/-

shh-/-, gli+/-

gli -/-

shh-/-m gli3 -/-

look like

Answer 23

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

Question 24

what happens between difference of reduced shh and enhanced in regards to dentate gyrus

Answer 24

reduced-depletetion of dentate gyrus

increase-increased dentate gyrus granule cells

Question 25

encepholoy

Answer 25

product of pover production of CNS progenitor cells-link between Hh and stem cell proliferation

Question 26

holoprosencephaly

Answer 26

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?

Question 27

smoothened and hpe

Answer 27

smoothened is critical drug/toxicologal target

not targeted by shh-targeted downstream

other ligands can turn smo on-neuro defects

Question 28

what is required for production and secretion of mature shh+ how+what loss of function cholesterol

Answer 28

cholesterol!

Hh is usually large precurosor that is cleaved when added to cholesterol

results in HPE-probably due to lack of dhcr7 gene

Question 29

Hh disease facts due to increased signalling

Answer 29

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)

Question 30

gli 3 diseases +congeniality

Answer 30

all are congenital

mutations lead to loss of gli3rep-three auto dominant dryness

overlord of digits, limb/brain defects

Question 31

gliblastoma

Answer 31

due to increase of hh signaling

agresseive cns tumor

Question 32

Medullablastoma

Answer 32

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

Question 33

wnt/wingless

where are two intracellular pools of beta catenin

Answer 33

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

Question 34

wnt pathway w/ wnt

Answer 34

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

Question 35

want pathway w/o b-catenin

Answer 35

tcf/lef proteins associate with groucho/grg to block target gene expression

tcf/lef proteins are bi-functional trx factors

Question 36

destruction complex + what happens after

Answer 36

axin, APC, Gsk3 phosphorylate beta cattiness when no wnt

beta-catenin-P is substrate for beta TrCP degredation

Question 37

PP2a

Answer 37

-PP2A removes P form beta catenin

Question 38

wnt + cancer

Answer 38

simlpy changing beta catinin stability can cause cancer

-can result in constitutive activation-cancer

Question 39

APC and cancer

Answer 39

linked with collateral cancer-too much beta catenin

Question 40

what is canonical wnt pathway

Answer 40

regulation of beta cat into the nucleus

Question 41

what is noncanonical wnt pathway

Answer 41

no beta cattiness or things that effect beta catenin

has tissue polarity function