Molecular Pattern Formation Flashcards
Trisomy 13 phenotype:
- midline defects
- Cleft lip, palate
- holoprosencephaly (single ventricle)
Trisomy 18 phenotype:
- Intrauterine growth restriction
- Clenched hands
- Low set ears
Mutations in specific transcription factors can cause developmental disorders in:
- overall body patterning or genesis of specific organs
How many gene deficits are sufficient to interrupt specific organ development?
one (single gene deficit)
A teratogen is:
- an agent which can cause a birth defect.
- It is usually something in the environment that the mother may be exposed to during her pregnancy.
When do teratogens act?
- during critical times of organ formation.
Most major birth defects arise from genetic or environmental abnormalities during what time period of gestation?
the first two months
What weeks of pregnancy is the embryo not susceptible to teratogens?
- first two weeks; “pre-differentiation” phase.
- embryo will recover cells damaged or killed.
Risks of birth defects from many teratogens are highest when?
- in the embryonic period
- 3-8 weeks in humans
Transforming growth factor beta (TGF-b) binds to what kind of receptors?
serine-threonine kinase receptors
Fibroblast growth factor (FGF) binds to what kind of receptors?
tyrosine kinase receptors
Steps in TGF-beta signaling pathway:
- TGF-beta ligands bind as dimers to a ser/thr kinase type II receptor.
- type II ser/thr kinase receptor dimerizes with and phosphorylates a type I ser/thr kinase receptor.
- phosphorylated type I ser/thr kinase receptor phosphorylates folded Smad2/3.
- Phosphorylated Smad2/3 unfolds and dimerizes with Smad4.
- Smad2/3-Smad4 dimer migrates to nucleus to alter gene expression.
Antagonists of TGF-beta peptides can regulate TGF-beta activity via:
- binding TGF-b receptors
- preventing formation of active TGF-beta ligand dimers
Steps in FGF-Heparan Sulfate signaling pathway:
- FGF monomers bind to heparan sulfate side chains of a transmembrane protein
- heparan sulfate transmembrane protein presents FGF monomers to tyrosine kinase receptors, activating the signaling pathway
- presents FGF monomers in a dimer-like fashion
What is this image showing?
- Two TFs are required for two early embryonic lineages are initially coexpressed but expression becomes gradually restricted (via reciprocal inhibition) even before trophoblast and inner cell mass cells become completely sorted.
- Changes in molecular identity of cells occur prior to organization of specific cell types in early embryonic regions.
Process of gastrulation:
- Endodermal cells arise from the epiblast and enter the embryo via the primitive node and replace the hypoblast.
- Mesodermal cells arise from the epiblast and enter the embryo via the primitive node and spread.
What is the is area of active invagination into the inner embryo during gastrulation?
the primitive node
A mutation in a gene encoding for what protein will prevent formation of the primitive streak and production of the mesoderm?
- “nodal” protein
- a TGF-beta related peptide
What TGF-beta peptide is the major determinant of mesoderm formation?
nodal
“Nodal” protein expression is necessary for the development of what three embryonic structures?
-
anterior visceral endoderm (AVE)
- required for differentiation of anterior structures (head, brain, etc.)
- mesoderm
- primitive streak
Mesoderm gives rise to:
- most connective tissue
- induces nervous system formation from overlying ectoderm
After “nodal” protein induces formation of the anterior visceral endoderm (AVE), what does AVE do?
- produces inhibitors that suppress “nodal” protein expression in most of the embryo except for a small portion.
- This small portion is where the mesoderm and the primitive streak forms.
BMP4 in the human embryo:
- inhibits “nodal” protein
- suppresses mesoderm and nervous system formation
- promotes epidermis formation
BMP-4 is what kind of peptide?
TGF-Beta
BMP4 in the human embryo is antagonized by:
chordin, noggin, and lefty
What do the chordin and noggin proteins do in the human embryo?
- bind to BMP-4 and prevent its association with BMP receptors.
- “nodal” protein expression expands
- dorsal mesoderm and nervous system forms
Goosecoid protein in the human embryo:
- a transcription factor that induces anterior mesoderm formation.
- expressed with chordin and noggin
- aids in the development of the head
Too much of what protein will lead to two heads and overproduction of head tissue?
- goosecoid
- directs anterior mesoderm formation/head patterning
What transcription factor gene produces a tail-less phenotype/much-reduced posterior mesoderm?
brachyury
What three proteins are required for proper development of the lower limbs/posterior mesoderm?
chordin, noggin, and brachyury
Lack of posterior structure development (leg defects, decreased posterior mesoderm) is due to too little of what proteins:
chordin, noggin, brachyury
What protein is required for proper development of the head/anterior mesoderm?
goosecoid
FGF is also expressed in the primitive streak cells giving rise to mesoderm.
What are its two major functions here?
- leads to left-right sidedness by inducing/maintaining a second region of “nodal” protein expression
- promotes continued chordin and noggin expression, which promotes more posterior mesoderm production and neural tissue development from ectoderm
Where is endogenous retinoic acid produced during embryogenesis and tissue development?
- by RAldh2 in the somites adjacent to the neural tube
Increased levels of retinoic acid in the embryo environment can lead to:
- reduced posterior structures
- increased RA prematurely inhibits FGF, which is involved in 5’ HOX gene activation.
- 5’ HOX genes never activated, posterior regions fail to develop properly.
What are two exogenous sources of retinoic acid?
- accutane
- high doses of vitamin A
Retinoic acid role in normal embryonic development:
- gradually inhibits FGF
- activates nuclear retinoic acid receptors
Retinoic acid role in abnormal embryonic development:
- prematurely inhibits FGF:
- 5’ HOX genes never activated
- deficits in posterior structure result
FGF are involved in the activation of what genes necessary for proper posterior development in the embryo?
- 5’ HOX genes
- necessary for proper patterning of the posterior portion of the embryo
What three proteins can antagonize (inhibit) BMP-4, thus preventing its dimerization with another BMP-4?
chordin, lefty, noggin
