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developmental biology
Limb development/myo-/osteogenesis
25
Biology
Undergraduate 3
12/09/2008

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Cards

Term

stylopod

 

zeugopod

 

autopod  

Definition

stylopod- humerus/femur

 

zeugopod- radius-ulna/tibia-fibula

 

autopod- tarsals/metatarsals 

Term

 

 

Patterning along which 3 axes?  

Definition

dorsal-ventral = palm-knuckles

 

anterior-posterior = thumb-pinkie

 

proximal-distal= shoulder-finger/hip-toe 

Term

 

 

 

Limb field

Definition

limb field = precise location at which limb forms

    - "free limb" + peripheral tissues = limb field 

    - peripheral tissues = shoulder girdle/peribrachial         tissues

    

*tissues can be removed without defects --> all tissues in area can form limb*

Term

 

 

 

Limb bud  

Definition
limb bud=
 
def. somatic lat. plate mesoderm/somitic mesenchymal cells accumulate under ectoderm to create CIRCULAR BULGE   
Term

 

 

 

LIMB BUDS COMPRISED OF TWO TYPES OF TISSUES

 

Definition
1) somatic mesoderm of lateral plate (skeletal elements) 
 
2) abaxial myotome cells from somite(muscle elements) 
Term

 

 

Compensatory powers of limb buds/fields 

Definition
 - when limb field first forms, any 1/2 of limb disk can form new desk
 
-if grafted to new site, supernumerary limbs will form
 
- if field is split (border b/w split regions), multiple limbs will sprout at site  
Term

 

 

Limb field in Tetrapods  

Definition
-4 limb buds
-2 pairs positioned opposite each other (across midline)
    - pos. adjacent to specific somites  
 
-placement of limb buds differs with respect to somite level in different species, but POSITION IS CONSTANT WITH RESPECT TO HOX EXPRESSION
    - forelimb bund at anterior region of Hoxc6 gene 
 
Term

 

 

Early limb bud formation-

Fgf10  

Definition
-earliest stages of bud formation caused by restriction of Fgf10 expression 
    - first expressed throughout lat. plate mesoderm,     but prior to limb formation, restricted to region
    where limb will form
        -restricted by Wnt Expression 
        - Wntc8 in hindlimb
        - Wnt2B in forelimb
 
-Fgf10 initiates limb development along the flank --> initiates interactions between ecto/mesoderm
 
*if Fgf10 beads places under ectoderm, ectopic limbs WILL form!  
  
Term

 

 

Fgf10 patterning in limb field (cont'd)  

Definition
- stabilized Fgf10 in lat. plate mesoderm will signal ectoderm to make Wnt3A 
 
- Wnt3A drives Fgf8 expression
 
-Fgf8 drives Fgf10 production  
 
-FEEDBACK LOOP TO KEEP FGF10 STABLE IN PLATE MESODERN  
Term

 

 

 

SPECIFICATION OF LIMBS (FORE- VS. HIND-LIMB) 

Definition
- specification of fore-/hindlimbs through Tbx expression (TFs)
    - Tbx5 in forelimb
    - Tbx4 in hindlimb
 
-specification (via Tbx) occurs BEFORE Fgf (Fgfs drive limb formation) expression occurs 
 
... limbs already specified once they begin to form  
 
- structure of supernumerary limbs dependant on which Tbx field they are closer to 
 
*chick made to express Tbx4 --> anterior limbs became legs instead of wings*  
Term

 

 

 

Apical Ectodermal Ridge (AER)  

Definition
-Fgf10 from mesenchyme(lat. plate mesoderm) causes overlying ectoderm to form AER
 
*interaction between adjacent mesoderm and AER critical*
    - keeps distal mesenchyme (PROGRESS ZONE)        proliferative 
 
-AER directs growth and patterning of the limb by:
(1)maintaining expression of molecule that gen. A-P axis
(2) interacting with proteins specifying the A-P/D-V axes  
    
Term

 

 

 

4 Conditions of AER:  

Definition
  1. if AER is removed, growth of limb stops 
  2. if extra AER, distal structures are formed
  3. limb is regionally specified by mesenchyme
  • if leg mesenchyme is placed just under AE at forelimb height, toes will form on wings 
    4. if non-limb mesenchyme placed beneath AER,     the AER degenerates and growth stops
Term

 

 

 

 Importance of FGFs

 

Definition
  • FGFs needs for maintenance and induction of AER 
  • FG10 from mesenchyme induces formation of FGF8 in the ectoderm of AER
    • positive feedback
    • FGF10 --> Wnt3A --> FGF8 --> FGF10...  
  • feedback process keeps mesenchymal cells proliferative so limb lengthens proximal to distal
Term

 

 

 

P-D Polarity and Specification

Definition

 

  • does AER or mesenchyme specify structural polarity of the limb?
  • If AER removed at different times, then development stops at different lengths
  • **AER does not specify structure--> MESENCHYME DOES**
  • ***switching older AER for newer doesn't induce distal structures earlier 
  • IF progress zone (mesenchymal) of early stage embryo placed on a late stage embryo, P-D duplication
  • IF PZ (mesenchymal) of late stage placed on early embryo, distal structures form immediately 
Term

 

Mesenchymal Specification

2 models:

 

(1) Time - Progress Zone Model

(2) Space- Early Allocation and Progenator Expansion model  

Definition
Term

 

 

 

(1) Time Model - explains mesenchymal specification  

Definition
  • determined by HOW LONG (i.e. time) cell remains in proliferative PZ
  • PZ stays same size even though cells in region very mitotically active--> b/c cells constantly move out of region
  • cells that leave cause limb to lengthen
  • **the longer a celll state and te more mitosis it undergoes, the more distal a structure it forms**
  • removal of the AER stops the clock so only proximal structures form 
Arguments AGAINST theory:
  • when marked with dyes, progeny of cells limited to particular segment of the limb
  • time spent in PZ did not specify cell position --> specification earlier!!!!  
Term

 

 

 

2. Space model of mesenchymal specification - Early Allocation and Progenatory Expansion Model  

Definition
  • all the cells in the limb SPECIFIED EARLY
    • subsequent divisions expand specified regions
  • stratified within the bud
  • AER drives proliferation, allows for expansion and survival of progenators 
Term

 

 

 

Hox expression in Proximal-Distal Axis  

Definition
  • Hox proteins are MOLECULAR DRIVERS OF STRUCTURE
  • HoxA-D prominent in FORELIMBS
    • Hox9/10 in stylopod
    • Hox11 in zeugopod
    • Hox12/13 in autopod 
Term

 

 

 

Homozygous mutation in Hox(A/D)13 protein 

Definition
  • supports Hox expression theory that Hox genes specify structure
  • Hox13 mutuation= distal autopod defects (polysyndactaly)
Term

 

 

 

Hox gene KO experiments  

Definition
  • Hox11 KO: stylopod forms, zeugopod does not
  • Hox10 KO: no femur, patella, etc.
Term

 

 

 

Zone of Polarizing Activity (ZPA)  

Definition
  • location: @ posterior juncture b/w limb bud and body wall 
  • transplation of ZPA from posterior to anterior reverses polarity --> result? mirror image duplication of digits 
Term

 

 

 

What specifies ZPA?  

Definition

Shh!!!!

 

  • defines ZPA
  • necessary/sufficient for polarizing activity
  • cells that artificially secrete Sh can duplicate transplanted ZPA  
Term

 

 

 

 Hx Mutation

Definition
  • ZPA definition by Shh confirmed with Hx mutation
  • Hx mutuation = naturally occurring mouse mutation, hemimelic extra toes
  • mirror image duplication of digits 
  • tracked to a point mutation in the Shh Limb specific enhancer region (upstream from Shh gene)
  • Allows for aberrant transcription in anterior regions 
Term

 

 

 

Shh Mechanism  

Definition
  • cells secreting Shh incorporated into final limb structure --> become bone,muscle, skin of posterior limb
  • don't die like the AER cells (i.e. don't undergo apoptosis)
  • muscle, bone,skin of digits 4 & 5 came from Shh secreting cells 
  • polarity determined by how long Shh was expressed vs. concentration seen by a cell
    • autocrine signaling
    • digit 5 expresses Shh longer than digit 4
    • Digit 3 some Shh expression and a lower gradient signal caused by diffusion of Shh from ZPA
    • Digit 2 sees only Shh coming from gradient in ZPA
    • digit 1 specified independant of Shh
Term

 

 

 

Digit Identity  

Definition
  • DIRECTED BY THE WEBBING BETWEEN THE DIGITS BEFORE IT IS REMOVED
    • BMP-mediated
    • ***BMP gradient driven by Shh***
  • webbing gives identity to digit forming anteriorly to it 
    • change ID if remove webbig
    • change ID if alter BMP expression/signaling
    • Noggin-overexpression inhibits BMP
      • Noggin overexpression b/w 3 and 4: 3rd transformed anteriorly to digit 2 
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