Molecular Genetics of Pattern Formation I Flashcards
Robertsonian translocaion
long arms of 14 fused to 21
-leads to downs
Aneupolidy is typically…
embryonic lethal
-13 and 18 can survive post fatally
trisomy 13
midline defects, clef lip, csn malformormations, holopresencpahy-single ventricle
trisomy 18
clenched hands, low ears, rocker bottom feet
signle gene mutations causing genetic defects
especially important in SHH and HOW
-also have organ specific ones
Large doses of intrauterine vitamin a (vit a aka)
facial abnormalities, neural tube defects,
- in acne meds
- retinoic acid
when is risk of brith defects from teratogens highest
3-8 weeks
Signal transduction via receptor kinases pathway
ligand binds to receptor, dimerization, signalling cascade involving phosphrylation ensures, activated protein complex is a TF
Where does retinoic acid bind
to nucelar receptors always located in nuceleus
TGF beta signalling/SMADS pathway
draw slide 12
+main pathway for antagonism
TGf beta (can also be BMP4 or activin) binds to receptor
Second receptor recruited+TGF (or BMP4) binds+phosphorylates receptor
Recruits/Phosphorylates Smad 2 or 3
Smad 2/3 oligomerizes with Smad 4 and goes to nucleus where can recruit other gene proteins and activate trx of specific target gene
use something that antagonizes tgif-beta/bmp4
Fgf heparan sulfate
Fibroblast growth factors
4 receptors
used in critical early axis format and for dev of several organs (bone and cartilage)
Heparan sulfate on cell surface helps FGF present to Tyrosine kinase receptors and helps active dimeric receptor even when FGF is monomer
Preimplantation timeline
First meiosis-several divisions, morula, then blastocyst-day5
ICM embryoblast+trophoblast
when does implantation occur
what can icm cells become
day 6
ICM cells can become ecto, meso, or end
Two TFs i eqrly embryonic cell lineages
all cells express both at moral
some cell preferentatillly 1 vs other at 16 cells
the cells segregate-one forms TE other forms ICM
-happens again to form endoderm vs epiblast
eventually both cells restrict each other with reciprocal inhibition
2nd week germ disc’s mesoderm
Little embryonic mesoderm-forms connective tissue, control nervous system formation
what are embryonic endoderm dn mesoderm derived from
cell that enter primitive streak
endodermal enter first during gastrulation
-mesdermal arise from epiblast and enter, spread extensively
engrossing of epiblast cells are thought to replace hypoblast cells (become yolk sac lining)-ingressing cells fan out to form mesodermal layer
embryonic node
area of active invagination into inner embryo
Nodal
TGf-b related peptide
expressed in posterior region of embryo called “node” where mesoderm will form
when knocked out primitive streak does not form
Pattern anterior visceral endoderm-needed for anterior structure differentiation
wants more mesoderm
Nodal expression (draw slide 19)
broad early, induces anterior visceral endoderm-produces new signaling molecules that establish anterior-posterior embryonic axis/promote afterior differentiation
Induced ave-produces inhibitors that suprpres nodal expression in most of embryo exposept in posterior end
-At this place, the node region, nodal expression increases to the threshold level needed for mesoderm to form a dn for primitive streak formation to begin
+flattens?
BMP4
suppresses mesoderm and nervous system formation and promtes epidermis
antagonized by chordin and login
-bind to BMP4 and prevent association with receptor
opposite action of nodal
-wants less mesoderm, nodal wants more
not expressed where primitive streak formed (i am pretty sure)
Goosecoid
expressed in node-TF that allows anterior structures to be induced in mesoderm-interact with cells controlling head structures
Nodal expression in node begets
expression of noggin and chords
bind to BMP-4 and prevent association with BMP receptors-allows nodal expression to expand
Brachyury
Knockout results in much-reduced posterior mesoderm
-tailless phenotype
relation of mesoderm, bmp-4, chordin, noggin, brachyury, goosecoid, FA, and FGF
Mesoderm increase
BMP, chordin, noggin, brachury, goosecoid decrease
mesiderom decrease
RA and FGF decrrease
proteins known for dev of anterior structures
chordin, noggin, brachury, goosecoid
too much goosecoid results in
two heads
Too little chords, noggin, brochure results in
posterior mesoderm never forming
can also be rbecuase too much runic acid/too little FGF
sironomelia-fusion of limb buds
FGF functions + where expressed
expressed in primitve streak-gives rise to mesoderm
induces main second region of nodal expression-leads to left/right sidedness
FGF in mesoderm promotes continued chords and noggin expression, inhibits BMP4
-inhibiion of BMP 4 promotes more mesoderm as well as neural tissue development
What is expressed in primitive streak
Nodal and FGF
retinoic acid
produced and normally active in only small areas of embryo-activates nuclear RA receptors
endogenous synthetic and degradative enzymes for RA-if mutated-major abnormalities occur if too much RA
-espeically in posterior structures becoming anterior
RA is teratogen
After RA exposure-RA receptors are activated on cells that do not normally see RA
Vitamin A is rpecursor to RA-high exposures are very bad
retinoic acid interaction+what happens if 1 wins over other that isn’t supposed to
recipricol inhitory interactions with FGF isoform
RA produced more anteriorly, FGF more posteriorly
-RA turns off FGF8 from rostral to caudal
Maintenance of posterior FGF signaling is needed for posterior structures to develop
-too much RA-FGF turns off prematurely-problems with posterior development
HOX expression patterns in embryo
and how relates to FGF
Several hox genes are linearly arranged in clusters
5’ hox genes direct development of posterior structures
more FGF exposure needed to activate 5’ HOX genes needed for posterior dev
- too much RA-FGF turned off prematurely
- 5’ hox gene activation doesn’t occur and there are defects in posterior structures that these genes control
Gentic causes of birth defects
robertsonian translocation, error in kiosks one, isochromaseom-downs
trisomies-patau (13) edwards (18)
Environmental causes of birth defects
tertogens, alocol, retinoic acid, many more
Teratogen affecting organs one at a time during dev
weeks 3-8-wmveto sec
days 15-60 organ specific
days 20-36 ears, eyes, upper/loewr limbs
Major effects of rinoic acid as teratogen
RA tug of war with FGF
- RA is for anterior
- FGF for posterior
Increase RA and decrease FGF
-defects or absence of posterior structures
Aspects of TGF/FGF signaling cascades
TGF-B signalling proteins-nodal, BMP4, activin
- nodal inhibits mesoderm formation
- ligands bind to TGF2 receptors, recruits P, ligand binds to other half and P does too, ruer SMAD2/3, dimerizes with SMAD 4-enters nun
FGF (and TGFB) is a tyrosine kinase receprotr
- results in axis dev, bone and cartilage dev
- GAT heparin thing-presents FGF to receptor even if monomer-allows activity
Changing role of TGF peptide nodal at different times in dev
increase nodal
- anterior visceral endoderm (AVE)
- inhibits nodal resision-anterior region
Nodal expression localized to small end at posterior
-node reaches threshold level-allows for mesoderm and primitive streak formation
nodal negative mice-no mesoderm or primitive streak
mechs that lead to deficient posterior mesoderm formation
Ra increase and FGF decrease
-Goosecoid-TF that allows anterior structures to be induced in mesoderm moving anteriorly
Nodal+BMP-4-have opposite effects
-nodal-mesoderm increase, neural tissue formation
BMMP-4-supresses mesoderm and neural tissue formation
Node-nodal, noggin, chordin, goosecoid
BMP4-boradly experssion in epiblast
Defiecent poster mech
- decrease chordirn, FGF, noggin
- increase RA
Brachury decrease(TF expeeression in poseterior mesoderm)
Retinoic acid as a teratogen in terms of FGF and homeobox
Increase RA, decrease FGF
more FGF needd to activte 5’ hox genes
increase RA, FGF turn off permanent (if too much)
5’ is poseterior, 3’ is anterior
Changing role of TGF peptide nodal at different times in dev
increase nodal
- anterior visceral endoderm (AVE)
- inhibits nodal resision-anterior region
Nodal expression localized to small end at posterior
-node reaches threshold level-allows for mesoderm and primitive streak formation
nodal negative mice-no mesoderm or primitive streak
mechs that lead to deficient posterior mesoderm formation
Ra increase and FGF decrease
-Goosecoid-TF that allows anterior structures to be induced in mesoderm moving anteriorly
Nodal+BMP-4-have opposite effects
-nodal-mesoderm increase, neural tissue formation
BMMP-4-supresses mesoderm and neural tissue formation
Node-nodal, noggin, chordin, goosecoid
BMP4-boradly experssion in epiblast
Defiecent poster mech
- decrease chordirn, FGF, noggin
- increase RA
Brachury decrease(TF expeeression in poseterior mesoderm)
Retinoic acid as a teratogen in terms of FGF and homeobox
Increase RA, decrease FGF
more FGF needd to activte 5’ hox genes
increase RA, FGF turn off permanent (if too much)
5’ is poseterior, 3’ is anterior
