Matise - Sonic Hedgehog Flashcards
ZPA
location at which shh is expressed and also determines the polarity of the digits. If you introduce a second ZPA into a part of the body then you will see duplication of things. If we get rid of ZPA but just introduce Hh then the animal will still be fine.
ccyclopamine
binds to Smo and doesn’t allow it to work properly. Even in the presence of HH
Hedgehog
Basically the process occurs in the primary cilium. Whats happens is that there are these Gli proteins that can either be repressors or activators depending on if they are phosphorylated/partially cleaved or not. If they are cleaved then they are repressors, but if they are not cleaved then they are activators. They bind to the same gene sequence so all the leaving does is recruit different proteins to the site (coactivators maybe?). With hedgehog is bound to Ptch, Ptch can no longer inhibit Smo and Smo moves to the tip of the ptimary cilia and causes Gli to not be cleaved so it is an activator. This causes transcription to occur
IFT
required for proper functioning og HH because it shuttles GliA and GliR into the nucleus
3 types of hedgehog
Indian - cartilage and bone
Sonic - CNS
Desert - peripheral nerves
Role of cilia in normal and abnormal human function
1) numerous cilia are involved in Hh signaling
2) cilia localize signal transduction pathways
3) Humans with ciliary defects (ciliopathies) can have problems with many things.
Difference between limb development and ventral midline structure (CNS) development
Limb: don’t need GliAct. If you have too much Shh then you will too much of things. If you have too much Gli3 (repressor) then you will have too little of things. You don’t even need an active Shh if the Gli3 is mutant because you don’t need GliAct
Ventral midline structures: Need the GliAct. Otherwise things won’t develop.
Holoprosencepphaly
incomplete midline formation during forebrain development. Basically it is caused by a mutation in the Shh pathway. Can be mutation in Shh, Gli2, or anything that interferes with the ability of Hh to activate Smo. It will cause developmental disorders characterized by incomplete midline formation. It can have many other symptoms like cyclopia, single forebrain vesicle etc.
Often the mutations are limited to the brain/face, which indicates that genes have a different sensitivity to gene dosage.
cholesterols role in Shh processing
Hh actually starts as a longer precursor and needs to be cleaved into its active form. This occurs with the help of cholesterol which then binds to the C-terminal. Cholesterol is actually the active signaling species
Smith-Lemli-Opitz Syndrome
Loss of function allels of the DHCR7 gene. DHCR7 encodes an enyme that is critical in cholesterol synthesis. Therefore, a mutation in this will cause similar symptoms to lack of Shh. You can’t take statins while pregnant because it will lower cholesterol levels
Gli3Rep mutations
All autosomal dominant
- Greig Cephaloopolysyndactyly (GCPS)
- Pallister-Hall (PHS)
- Postaxial Polydactyly (PPS) - Gli3 haploinsufficiency (heterozygous) will cause more than 5 fingers/toes
Medullobllastoma
tumor arising in the cerebellum during development. Many people with this cancer have PTCH1 mutations. Can also get MB with mutation in SMO. If you think about it, if PTCH is mutated then it can’t inhibit SMO. When we don’t inhibit SMO then it goes wild and makes GliAct.
B-Catenin and Wnt
When Wnt is bound to Frizzled/Frz and Arrow/Lrp it will cause the “destruction complex” (Axin, APC, Gsk3) to disassociate and interrupt B-catenin phosphorylation/degradation. B-TrCP is the thing that actually degrades it. PP2A causes the B-catenin to be further dephosphorylated. When B-catenin is not phosphorylated it enters the nucleus and binds to Tcf/Lef and makes it dissociate from the DNA and transcription will be active. When there is no B-catenin, Tcf/Lef proteins associate with Groucho/Grg cofactors
Wnt binds Frizzled and Arrow –> destruction of death complex –> B catenin is not phosphorylated and destroyed –> B catenin enters the nucleus –> B catenin binds to Tlf/Lef and causes target gene expression
APC mutations
Strongly linked to colon cancer. Makes sense because APC is part of the destruction complex. If that complex isn’t working then B-catenin will enter cell and transcription will be on.
Canonical vs. non-canonical pathways of Wnt
When Wnt binds it doesn’t necessarily have to go through B-catenin to cause the cellular response. If it doesn’t go through B-catenin, then it goes through the non-canonical pathway.
