Genetic and Environmental Influences on Early Human Development Flashcards
Fewer than 1/2 fertilized human eggs implant and of that, what fraction will give rise to an infant?
1/3
Structural abnormalities that can be caused by genetic factors or by environmental factors, or both
Congenital malformations (present at birth)
About 6% of individuals are born with congenital malformations. What percentage of perinatal deaths are caused by such abnormalities?
20%
The field that has emerged to study abnormal development in embryos
-investigates the causes of congenital abnormalities/birth defects
Teratology
7% of congenital abnormalities are known to be caused by
-can be chemical toxins, infections, or maternal deficiency
Teratogenic agents
Will often kill embryo in first two prenatal weeks or lead
to spontaneous abortions in the first 6-8 weeks of gestation
Teratogenic agents
Teratogens can cause organ-specific abnormalities from days
15-60
Genetic factors cause 20-25% of birth defects, where as environmental factors account for
5-15%
Most cases of Down syndrome are caused by a deficit in
-produces gamete with 2 copies of chromosome 21
Meiosis I
Another cause of Down Syndrome that occurs when the q arms of chromosomes 14 and 21 fuse
-No symptoms
Robertsonian translocation
Has the symptoms of distinct facial features, congenital
heart disease, mental and growth retardation
Down Syndrome
Almost all alterations in chromosome number will be lethal in
Early embryo
Besides trisomy 21, what are two other trisomies where affected individuals survive post natally?
Trisomy 13 and trisomy 18
Can be a major result of abnormal genetic composition (esp. trisomy 13)
Midline defects
Cleft lip and palate and CNS malformations are characteristic of
Trisomy 13
Tend to survive longer with trisomy 18
Females
Characterized by intrauterine growth restriction, clenched hands, and low set ears
Trisomy 18
Single gene defects can interrupt
Specific organ development
Mutations in specific transcription factors can cause developmental disorders in overall body patterning or genesis of
Specific organs
A variety of teratogens (such as drugs) can affect development and lead to
Deformities
Act during critical times of organ formation
Teratogens
Nothing in weeks 1 and 2 of pregnancy is susceptible to
Teratogens
What is the most sensitive to teratogens throughout most of the pregnancy?
Central Nervous System
The risk of birth defects from many teratogens are highest during the
Embyonic Period (3-8 weeks)
Developed as sedative and insomnia treatment. However, if the fetus exposed at 24-36 days,
limb outgrowth is dramatically affected
-Does not effect subsequent digit development
Thalidomide
What are three major developmental signaling pathways?
-used at different steps in multiple tissues
- ) Transforming growth factor beta (TFG-β)
- ) Fibroblast growth factor (FGF)
- ) Retinoic Acid (RA)
A family of over 30 peptides that bind to serine-threonine kinase receptors
TGF-β
Made up of over 20 peptides that bind to tyrosine kinase receptors
FGF
Binds to nuclear receptors to regulate gene transcription, and has endogenous enzymatic control of its synthesis and degradation
Retinoic Acid (RA; derived from vitamin A)
Signal transduction via receptor kinases occurs when a ligand binds a receptor kinase in the cell exterior, causing a conformational change and phosphorylation cascade on the cell interior. Variations of this theme are used by
TGF-β and FGF pathways
Does not bind kinase receptors but instead binds nuclear receptors
-always located in the nucleus
Retinoic Acid
TGF-β ligands bind as a
Dimer
TGF-β binds to a type II receptor, which causes the receptor to recruit and phosphorylate a
Type I receptor
Phosphorylated type I receptor recruits and phosphorylates
Smad2 or Smad3
Phosphorylated Smad2 or Smad3 dissociates from the receptor and oligomerizes with
Smad4
Unfold when phosphorylated
Smads
Migrates to the nucleus, recruits other gene regulatory proteins, and activates transcription of specific target genes
Smad2(3)/Smad4 oligomer
Can antagonize action of the TGF-β peptide BMP-4 by binding to it and thus preventing BMP-4 dimer formation
Chordin, noggin, and lefty
What are the three TFG-like peptides we need to know
- ) TFG-β like (nodal)
- ) Mone morphogenetic proteins (BMP-4)
- ) Activins
Chordin, noggin, and lefty bind the BMP-4 monomer and prevent BMP-4 dimer formation by forming a dimer of their own, which can not bind/activate
BMP receptors
What are the four FGF receptors?
FGFR-1 through FGFR-4
Critical for early axis formation and for development of several organs, particularly bone and cartilage
FGFs
Helps present FGF to tyrosine kinase receptors and presumably helps stabilize the active dimeric receptor even though FGF is a monomer
Cell surface/transmembrane Heparin Sulfate
The inner cell mass (ICM) is the source of all
Embryonic tissues and stem cells
Changes in molecular identity of cells occur prior to organization of specific cell types in
Early embryonic Development
Early fetal lineages are already specified in a mixture of cells as noted by different transcription factor expression before they are sorted to
Different regions
This tissue will arise from the portion of the epiblast (blue) that is at the posterior end of the embryo via movement through the primitive streak
Mesoderm
Will form connective tissue and will control nervous system formation
Mesoderm
When does the primative streak form?
14 days in
The embryonic endoderm and mesoderm are derived from cells that enter the
Primative streak
First to enter embryo during gastrulation
Endodermal cells
Arise from the epiblast and enter the interior of the embryo, spread extensively, and give rise to dorsal and ventral derivatives
Mesoderm
What are some dorsal mesoderm derivatives?
Bone, cartilage, and muscle
What are some ventral mesoderm derivatives?
Kidney and blood
The area of active invagination into the inner embry
Node
A major determinant of mesoderm formation in the mammal
-mutation in mice caused a complete lack of mesoderm
The TGF-β peptide “nodal”
“Nodal” is expressed in posterior region of embryo called the
-where mesoderm will form
Node
Using the gene sequence of nodal as a probe, nodal expression was found in the
Primative streak
Acts to generally inhibit initial mesoderm and nervous system development
BMP-4
BMP-4 can be inhibited by the antagonists
Chordin, noggin, and lefty
Initially induced by nodal at an earlier stage, which then both limits nodal expression as well as contributes to anterior head structure formation
Anterior visceral endoderm (AVE)
“Nodal” expression begins even earlier and first induces another important region of the early embryo, which is called the
Anterior visceral endoderm (AVE)
The Anterior visceral endoderm (AVE) is required for differentiation of
Anterior Structures
Induced AVE in turn produces inhibitors that suppress nodal expression in most of embryo except for a small region at posterior end called the
Node
There, at the “node” region, nodal expression increases to the “threshold” level needed for mesoderm to form and for
Primative streak formation
Noggin and Chordin are produced at the
Node
A transcription factor that will allow anterior structures to be induced in mesoderm moving anterior
-Also produced at the node
Goosecoid
In addition to nodal, several other genes also affect mesoderm formation. One example of this is the T-box transcription factor
Brachyury
Knockout of brachyury in mice leads to deficient
Posterior mesoderm (“tail-less” phenotype)
Directs anterior mesoderm formation, which in turn directs head patterning
Goosecoid
Too much gooscoid can lead to
Conjoined twins
Sirenomelia defects reflect decreased posterior mesoderm and possibly result from too little
Chordin, Noggin, brachury, or FGF (or too much retinoic acid)
Expressed in the forming mesoderm and leads to the formation of right and left sides
FGF peptide FGF8
FGF in mesoderm promotes continued chordin and noggin expression, which in turn continue to inhibit
BMP-4
The inhibition of BMP-4, especially in the dorsal region, promotes more mesoderm production as well as neural tissue development from
Ectoderm
A major regulator of FGF is
Retinoic Acid (RA)
Endogenous RA is produced and normally active in only small areas of the embryo where it activates
Nuclear RA receptors RAR and RXR
Results in much reduced posterior structures and some transformation of posterior structures to anterior structures
Excess retinoic acid
A potent teratogen at very low doses
Retinoic acid
Despite this teratogenicity, 13-cis-retinoic acid is prescribed for
Acne (accutane)
Also teratogenic at very high concentrations (10,000 units/day) because it will alter in vivo retinoic acid levels
Vitamin A
Has reciprocal inhibitory actions with an FGF isoform
Retinoic acid
RAldh2 (synthetic RA enzyme) is present in somite-derived mesoderm and thus RA is made by somites adjacent to neural tube and released. This RA binds to RA receptors in “stem” zone containing
FGF expressing cells
Maintenance of posterior FGF is needed for the development of
Posterior structures
Gradually turns off FGF8 from rostral to caudal
RA
Since the body axis forms from rostral to caudal, RA gradually shuts off FGF8 in a tightly controlled manner that allows
Posterior structures to form
Needed to allow posterior structures to keep
forming normally, and if it is turned off prematurely, there will be deficits in these structures
FGF8
Excess RA will turn off
-results in posterior structure deficiencies
FGF8
Direct the development of posterior structures
5’ Hox genes
Causes FGF to turn off prematurely. Thus activation of more 5’ genes in the Hox cluster will not proceed, and as a consequence, posterior mesoderm will be reduced
Excess RA
