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Flashcards in Molecular Genetics of Pattern Formation Deck (16):

Down syndrome

-Deficits in Meiosis 1 leading to trisomy 21


-Can be caused by robersonian translocation of q arms of chromosome 14 and 21

   *Individual with translocation is asymptomatic

   *Can pass on fusion chromosome such that an extra copy of entire

    chromosome 21 is passed on 


  *Distinct facial features

  *Congenital heart disease

  *Mental and growth retardation 


Genetic Chromosomal abnormalities of Chromosome 13 and 18

-Usually, aneuploidies are embryonic letha. 

-Chromosome 13 and 18 aneuploidy can survive post-natally because these chromosomes don't have as many genes. 


-Trisomy 13

*Midline defects 

*CNS malformation

*Micropthalmia: small eye

*Holoprosencephaly: single ventricle 


-Trisoly 18 

*Intrauterine growth restrictions

*Rocker bottom feet

*Prominent occipital lobe

*Females survive longer 


Critical periods for Teratogens

1-2 weeks: embryo not susceptible to teratogens

2-8 weeks: risk of birth defects from many teratogens are highes 


i.e Thalomide intake during 3-5 weeks of pregnancy interfered with outgrowth of limbs 


Receptors used by 

  1. TGF-B
  2. FGF
  3. Retinoic Acid

  1. TGF-B
    1. Binds to serine/threonine kinase receptor
  2. FGF-B
    1. Tyrosine kinase receptor
  3. Retinoic acid
    1. Steroid and can go through membranes and get into nucleus
    2. Bind to nucleuar receptors to regulate gene transcription


Examples of TGF-B-like peptides 

  1. Nodal for mesoderm
  2. BMP-2
  3. Activins 


Process of TGF-B signaling mediated by SMADs

  1. TGF-B ligands bind as dimers to one serine/threonine kinase receptor
  2. .Recruit second receptor to make dimer receptor
  3. Receptors have kinase activity and auto-phosphorylate themselves.
  4. Phosphorylated receptors recruit and phosphorylate Smad2 or Smad 3 from the cytoplasm
  5. Smads in the un-phosphorylated form are folded up.Smads in phosphorylated form, unfold and bind binding partners aka other Smads
  6. They can enter nucleus and bind to TGF-B response elements to modulate gene transcription


BMP-4 antagonists and mode of action

Noggin and Chordin are antagonists 

1. Noggin and Chordin bind monomer of BMP-4

2. Create ligand dimer that cannot bind or activate receptor dimer


Interaction between FGF/Heparan Sulfate Proteoglycan


-Consists of transmembrane protein with heparan sulfate GAGs branching off. 



-Heparan sulfate GAGs attached to FGF monomers. (you don’t have dimerization of ligand like you did for TFG-B ligands)

-The heparan sulfate helps present the FGF ligand to the receptor (almost in a dimer like formation) to stabilize active dimer receptor even though FGF is a monomer. 


Nodal Expression and its process of action

  1. During day 5, within inner cell mass of blastocyst, nodal induces anterior visceral endoderm that establishes anterior-posterior axis
  2. Anterior differentiation begins
  3. AVE produces inhibitors of nodal in most of the embyro except a small region in posterior end
  4. In posterior, nodal expression increases to threshold level. 
  5. BMP-4 is being made broadly in embryo and it tends to oppose Nodal thereby suppressing mesoderm and primitive streak formation. 
  6. When nodal is turned on posterior region by AVE, noggin and chordin bind BMP-4 and release inhibition such that so that mesoderm and neural tube induction can occur. 
  7. Once primitive streak form and mesoderm migrates
    1. Goosecoid is also made and it is found in mesoderm migrating towards anterior region.
    2. You can help induce head structure by having it interact with AVE. 


Note: nodal, chordin, noggin, goosecoid are all made at the node. 



-T-box genes encode bracyhury 

-Brachyury is a transcription factor 

-Brachyury is expressed in posterior mesoderm 

-KO of brachyury in mice reduces posterior mesoderm and produces tail-less phenotype 


Too much Goosecoid

  1. Goosecoid is expressed on mesoderm that migrate to anterior region
  2. Goosecoid when interacting with AVE is involved in helping pattern the head 
  3. Overexpression of Goosecoid in rostral/anterior part of embryo results in double-headed phenotype. 



  1. ​Condition in which infants have fused hind limbs 
    1. Caused by deficiency in mesoderm production in posterior/caudal region of embryo 
  2. Can be caused by:
    1. Deficiency noggin/chordin BMP-4 antagonists
    2. Deficiency in Brachyury
    3. Deficiency in FGF
    4. Too much Retinoic acid 



Role of FGF in mesoderm formation 

  1. FGF isoform is expressed in node of primitive streak
  2. FGF isoform 
    1. Induces regional expression of nodal on a specific side of embryo to establish R and L axis
    2. Induces noggin/chordin production in posterior part of embryo to continue inhibition of BMP-4 so that mesoderm can form. 


Retinoic Acid and FGF

  1. RA gradually turns of FGF in anterior regions 
    1. If levels of RA are too high, FGF is turned off prematurely preventing FGF expression in posterior region preventing formation of posterior mesoderm 
    2. Results in deficits in posterior structures
  2. FGF graudally turns off RA in posterior regions
    1. FGF needed in posterior for posterior structures to develop because FGF turns on 5' Hox genes needed for posterior development. 


Role of Retinoic Acid during development 

  1. RA is expressed in very small area (anterior region of embryo)
  2. RA binds to RAR and RXR receptors on nucleus and control gene expression
  3. Enzymes control synthesis and degradation of RA


Endogenous and Exogenous Exposure of RA

  1. Endogenous
    1. RA levels can increase if there is a mutation in enzymes that degrade RA
  2. Exogenous
    1. Following exposure to RA, RAR and RXR receptors can be activated on cells that normally do not have them.
      1. Accutane 
      2. Vitamin A