Matise - Sonic Hedgehog Flashcards
Hedgehog pathway
Hh ligand binds Patched (Ptc) receptor. Ptc receptor normally represses Smoothened (Smo) by keeping it out of the cilia. When Hh binds, Ptc blocked, Smo can enter cilia activate Gli by preventing its cleavage into a repressor. So instead of Gli-rep, produce Gli-act, and can transcribe target genes.
Primary Cilia
Involved in Shh signaling. Ptc found in cilia, other signal transduction products are localized.
Intra-Flagellar Transport
Intra-Flagellar Transport (IFT) moves stuff up and down cilia. Normally, Ptc prevents Smo from entering cilia, so Gli is cleaved to Gli-rep. IFT shuttles Gli-rep down cilia to nucleus. When Hh binds, IFT allows Smo to enter cilia, cause Gli-act to be produced, shuttles down to nucleus.
Zone of Polarizing Activity (ZPA)
Region from which Shh diffuses, causing CNS development. But really Shh causes development (so if inject Shh somewhere without ZPA, still cause neural tissue growth)
Cyclopia/Holoprosencephaly
Caused by Shh knockout.
Holoprosencephaly (one brain ventricle)
Cyclopia (one eye)
Shh graded effect on digit development
Ratio of gli-act/gli-rep controls finger development. So where Shh binds, more gli-act, development; further away, less gli-act diffuses, more gli-rep present, no development.
Key: LACK OF GLI-REP IS WHAT CONTROLS FINGER GROWTH: if gli-rep present, no development, if absent, extra fingers. Shh can cause gli-act>gli-rep, but even without Shh present, if no gli-rep, will see polydactyly
Shh effect on CNS development
Like with fingers, lack of gli3-rep is responsible for overactivation of the pathway, not Shh. BUT for CNS, BOTH gli1/2-act and gli-rep absence are required for inducing midline structures (pituitary, hypothalamus, spinal cord).
Exencephaly
mega-brain, explodes out of skull due to extra growth. Caused by Shh overexpression in stem cells.
Holoprosencephaly
Caused by gli3-rep overactivation. Causes incomplete midline formation, ranging in severity from giant cyclops eye to unimolar tooth.
-Only affects CNS, not impairing limb development, since CNS needs Gli-act presence + gli-rep absence, limb just needs gli-rep absence.
Cyclopamine
Binds Smo, preventing gli activation, deactivating Hh pathway. Causes cyclopia
-potential anticancer use, by preventing Shh activation when undesired
Cholesterol + Shh
Mature Hh produced by self-cleavage and binding of cholesterol on C-terminus
-inactive without cholesterol, so lack of cholesterol/inhibition of cholesterol biosynthesis will prevent Shh activation
Smith-Lemli-Opitz Syndrome
Cholesterol insufficiency due to mutated cholesterol synthesis pathway gene prevents Shh formation.
-Statins are dangerous to pregnant women since they will repress Shh activation in fetus
Postaxial Polydactyly
Extra finger growth, caused by GLI3 mutation–>gli-rep insufficiency–>overactivation of Shh
Medulloblastoma
Cerebellar tumor associated with Ptc insufficiency and Shh pathway overactivation EVEN WITHOUT SHH PRESENT due to lack of Smo repression, overproduction of gli-act
Wnt/Wingless Pathway
Normal: Baseline B-catenin phosphorylation prevents it from entering nucleus, causes B-catenin degradation by B-TrCP; Tcf/Lef transcription factors associate with Gro/Grg repressors, preventing gene transcription
Activation: Wnt ligand binds Frizzled (Frz) and Arrow/LRP receptor. Dissociates the B-catenin phosphorylation complex (Axin/APC/GSK3), preventing phosphorylation (and activating PP2A, a phosphatase). Dephosphorylated B-catenin can now enter nucleus, bind Tcf/Lef to cause gene activation.
-So Tcf/Lef are like gli, can be act/rep depending on what binds
