Signaling Pathways In Development Flashcards
In adults, Hh and Wnt signaling are involved in maintaining ___ niches in ___, ____, and ____.
In adults, Hh and Wnt signaling are involved in maintaining SC niches in CNS, SKIN, and GUT.
Hedgehog Family:
Indian: necessary for ______
Sonic: necessary for _____
Desert: necessary for ____
Hedgehog Family:
Indian: necessary for DEVELOPMENT OF CARTILAGE AND BONE
Sonic: necessary for DEVELOPMENT OF CNS
Desert: necessary for DEVELOPMENT OF PNS
Simplified Hh Pathway:
No ligand: Ptc inhibits___, which prevents ___ activation, ____ acts as ______
Ligand: Ptc is occupied, ____ can go on and convert ____ to activator form.
Simplified Hh Pathway:
No ligand: Ptc inhibits SMO, which prevents GLI activation, GLI acts as REPRESSOR
Ligand: Ptc is occupied, SMO can go on and convert GLI to activator form.
Regulation of Gli/Ci by phosphorylation:
When Shh is not present, ____ p-lates Gli, which directs it to ______, where it’s ______ is _____ and subsequent protein is a __________.
Blocking of ____ activity on Gli will result in _____, which results in ____ ____.
Regulation of Gli/Ci by phosphorylation:
When Shh is not present, PKA p-lates Gli, which directs it to PROTEASOME, where it’s C-TERMINUS is CLEAVED and subsequent protein is a TRANS REPRESSOR.
Blocking of PKA activity on Gli will result in FULL-LENGTH GLI, which results in TRANSCRIPTION ACTIVATION.
Shh transduction components localize to the ___ ____. When Shh binds receptor, the complex _______, and ___ is able to move closer to ____.
Shh transduction components localize to the PRIMARY CILIUM. When Shh binds receptor, the complex INTERNALIZES, and SMO is able to move closer to GLI.
Shh is localized to ______ in the ____ region of ___ ___ and early ____
Shh is also expressed in ______ structures such as _____ and _____.
Shh is localized to ORGANIZING CENTERS in the POSTERIOR region of LIMB BUDS and early CNS
Shh is also expressed in VENTRAL MIDLINE structures such as NOTOCHORD and FLOOR PLATE.
Shh is a ____ morphogen. Shh diffuses _____ within the limb to form a gradient with [low] in _____ and [high] in _____.
Shh is a ZPA morphogen. Shh diffuses DORSALLY within the limb to form a gradient with [low] in ANTERIOR and [high] in POSTERIOR.
In areas of high [Shh], you will only have gli-______ present because HH will be occupying most ____, allowing _____ to keep gli ____.
In areas of low [Shh]. You will have only gli-____ present because fewer _____ are occupied, so you will have ____ in some cells.
Dual opposition of gli activity gradients regulate a set of target genes which will specify _____ (____ and ____)
In areas of high [Shh], you will only have gli-ACTIVATOR present because HH will be occupying most PATCH RECEPTORS, allowing SMOOTHEN to keep gli AS ACTIVATOR.
In areas of low [Shh]. You will have only gli-REPRESSOR present because fewer PATCH are occupied, so you will have REPRESSION in some cells.
Dual opposition of gli activity gradients regulate a set of target genes which will specify DIGIT PATTERNING (CELL PROLIFERATION and CHONDROGENESIS)
Three Main Gli Proteins:
- Gli_ is most important for repression
- Gli_ is almost fully degraded when Shh is unavailable, whereas Gli_ is only partially proteolyzed, so it can be a functional repressor.
- When Shh pathway is activated, Gli_ is turned on and produced. It’s acted upon by Gli_/_. In active pathway, ____ gli are functioning as ____.
- When no Shh is present, Gli_ is the major functioning protein, which functions as repressor
Three Main Gli Proteins:
- GliTHREE is most important for repression
- GliTWO is almost fully degraded when Shh is unavailable, whereas GliTHREE is only partially proteolyzed, so it can be a functional repressor.
- When Shh pathway is activated, Gli1 is turned on and produced. It’s acted upon by Gli2/3. In active pathway, ALL gli are functioning as ACTIVATORS.
- When no Shh is present, GliTHREE is the major functioning protein, which functions as repressor
Diseases associated with reduced Hh signaling can result from mutations in ____ transduction pathway components such as ____, ____ and _____.
Can also be associated with increased _____ activity, as a downstream effect of the above.
SHH KOs are ____, and have ____ + _____, the _______ _____ _Structures fail to develop. End up with smaller ____ and a solely-_____ neural tube.
Diseases associated with reduced Hh signaling can result from mutations in POSITIVE transduction pathway components such as LIGAND, SMOOTHIN and GLI.
Can also be associated with increased GLI3-REPRESSOR activity, as a downstream effect of the above.
SHH KOs are SMALLER, and have ONE EYE AND HOLOPROSENCEPHALY, the VENTRAL MIDLINE Structures fail to develop. End up with smaller SC and a solely-DORSAL neural tube.
Holoprosencephaly symptoms and cause
Cyclopia, single forebrain vesicle, absence of pituitary, corpus callosum, or optic nerves, midline cleft palate, single maxillary central incisor
- SHH protein haploinsufficiency
- Mutations in Gli2
- Anything that interferes with ability of Hh to activate Smo (such as CYCLOPAMINE), which binds smoothened and blocks it’s activity
Smo is a 7-helix _______ and it’s natural ligand is _____.
-_____ and ____ antagonize smo
Smo is a 7-helix GPCR and it’s natural ligand is OXYSTEROL.
-CYCLOPAMINE and JERVINE antagonize smo
Mature Hh protein is generated from ________ that undergoes ______ reaction that requires addition of ____. The processed form of the protein containing a ____ ___ ___ is the active signaling species.
Shh mutants in holoprosencephaly patients affects the ____ ____
Mature Hh protein is generated from LONG PRECURSOR that undergoes SELF-CLEAVAGE reaction that requires addition of CHOLESTEROL. The processed form of the protein containing a COVALENT CHOLESTEROL ADDUCT is the active signaling species.
Shh mutants in holoprosencephaly patients affects the AUTO-PROCESSING
Loss-of-function alleles of the _______ gene are associated with Smith-Lemli-Opitz Syndrome and ____.
____encodes enzyme critical in ____ synthesis; so lack of _____ can produce the same phenotypes as lack of SHH. _____-reducing drugs in the group known as _____ ____ ____ should not be taken by pregnant women.
Loss-of-function alleles of the DHCR7 gene are associated with Smith-Lemli-Opitz Syndrome and HPE.
DHCR7 encodes enzyme critical in CHOLESTEROL synthesis; so lack of CHOLESTEROL can produce the same phenotypes as lack of SHH. CHOLESTEROL-reducing drugs in the group known as HMG-COA REDUCTASE INHIBITORS should not be taken by pregnant women.
Diseases associtaed with increased/unregulated Hh signaling leads to _____ and ____, and can result from mutations in _____ transduction pathway components. ______ or other ____ inhibitors may have therapeutic benefits.
Example: mutations in _____ are linked to 3 ______ syndromes that show ____ and ___ defects: ____, ____, and _____.
Diseases associtaed with increased/unregulated Hh signaling leads to CONGENITAL DEFECTS and CANCER, and can result from mutations in NEGATIVE transduction pathway components. CYCLOPAMINE or other SMO inhibitors may have therapeutic benefits.
Example: mutations in GLI3 are linked to 3 AUTOSOMAL DOMINANT syndromes that show LIMB and BRAIN defects: GCPS, PHS, and PPS.
