Hedgehog Signalling Flashcards
what is hh signalling important for?
developmental patterning and also implicated in development and disease
what is hh?
acts as typical morophogen
in drosophila- wing patterning
in vertebrates - limb buds etc
what is morphogen signalling?
sending cells (secrete signal) and gradient forms based on uptake of signal by receiving cells
how is hh expressed in drosophila?
in wing expressed in posterior compartment, meaning gradient produced across anterior comparment
what are three other variations of Hh?
sonic hedghog
indian hedghog
desert hedghog
what are PTMs of Hh?
palitation on n terminal (for signalling function and signal uptake)
cholsterol addition to c terminal (for signal spreading and multimerisation, as well as ptc and smo interactions)
what is the hh pathwya process?
hh translated and transcribed, is in the ER, precursor protein and proteolytic cleavage occurs where hedge and hog domains degraded by the proteosome (based on cholesterol and HH-C)
traffick to membrane from release
what are the four key mechanisms for Hh release from the plasma membrane?
transmembrane molecule dispatched and secreted scube2 bind cholesterol moiety of hh
spontaneous soluble multimers
heparan suphate proteoglycan (dally) recruits liphorin apopliproteins to form lipoprotein particles
exovesicles from MVBs
what is transendocytosis of Hh in the producing cells?
apically secreted hh is endocytosed by producing cells and transendocytosed to basal side of the cells
what are the two models of apical/basal gradient?
- gradient is forming on apical side of the tissue
2. yes apical secretion , but gradient actually forms on basal side of tissue
what is hh pathway when hh not present?
hedge not bound so ptc represses smoothened
blocking of smoothened trafficking to membrane leads to degradation
hh signalling complexes phosphorylate ci via kinases (cos2 main scaffold and targets ci to proteosome)
what is hh pathway when hh present?
binds to pedges and leads to smoothened which is transported to membrane
pedged endocytosed and degraded then upon recruitment to membrane, events occur at complex is different when associated with cytoplasm
smo relocates to membrane and leads to associated with hh signalling complex and theres phosphorylation of cos2 and sufu which releases unphosphorylated ci
describe signallign transduction in vertebrates
at primary cilium and is microtubule dependent
hh binding leads to increased cilia dwell time, dissociation of sufu/gli complex
what are three ways a morphogen signal can be transferred?
diffusion
relay
protrusions
how can we distinguish between diffusion morphogen transport and protrusion transport?
cytoneme presence
what are cytonemes?
filopodia like structures that orient toward source of morphogen
how does cytoskeletal regulatoin control filopodia formation?
small rho-gtpases regulate cytoskeleyon and these are molecular switches
whogdp to rho gtp
gef and gap
how are filopodia formed?
cdc42 recruits proteins to site of protrusion
there are proteins for parallel actin bundles, actin polymerisation and actin membrane interactions
what is the process of actin polymerisation?
nucleation, elongation, branching nucleation, enhanced elongation
which regions can cytonemes be found in hh signalling?
LECs and histoblasts
what is the relationship between cytoneme formation and hh activity gradients?
cytoneme formation correlates with establishment of hh activity gradient in space and time
how is hh actually transported?
in exovesicles which are created in MVBs via endocytotic pathway and cd63 is marker for exosomes
how does morphogen signal reach target cells?
developing air sac interacts with neighbouring cells to expand in the correct direction
cell-cell interactions are crucial for this and it is a split-gfp system (GRASP)
what are two other signalling processes that cytonemes are implicated in?
notch and wnt
what is signal transport via relay?
c elegans blastomere example
polarity in embryos
