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Limb Patterning: Proximal-Distal Axis. Gilbert - Chapter 16 Do you want to hear a talk from an ASTRONAUT 4/17??. Today’s Goals. Become familiar with several aspects of limb formation in the tetrapod Limb initiation Forelimb vs. hindlimb Where to make a limb? Limb patterning

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limb patterning proximal distal axis

Limb Patterning: Proximal-Distal Axis

Gilbert - Chapter 16

Do you want to hear a talk from an ASTRONAUT 4/17??

today s goals
Today’s Goals
  • Become familiar with several aspects of limb formation in the tetrapod
    • Limb initiation
      • Forelimb vs. hindlimb
      • Where to make a limb?
    • Limb patterning
      • Dorsal/ventral
      • Anterior/Posterior
      • Proximal/distal
generating limb axes
Generating Limb Axes
  • Classical embryonic manipulations from the dating from the 1940’s
    • John Saunders
    • Series of surgical rearrangements that later became the basis for what we know about molecular signals in limb formation
    • He identified specialized areas in the limb that were necessary for development of the different axes
proximal distal axis
Proximal Distal Axis
  • Growth along P-D axis made possible by interaction between 2 tissues
  • Apical ectodermal ridge (AER)
    • Thickening of ectoderm at distal tip of limb bud
    • Very important for several aspects of limb formation
  • Progress zone (PZ)
    • Mesenchyme directly underneath AER
    • Proliferates to lengthen the limb bud
experimental manipulations
Experimental Manipulations
  • Remove AER at any time
    • Distal limb development ceases
  • Graft extra AER to existing limb
    • Extra distal structures form
  • CONCLUDE:
    • AER is necessary and sufficient for distal limb formation
more experimental manipulations
More Experimental Manipulations
  • Remove PZ from wing, replace it with leg PZ
    • Toes form at distal tip of wing!
  • Remove PZ from wing, replace with mesenchyme from non-limb
    • Limb development ceases, AER disappears
  • CONCLUDE:
    • PZ involved in specifying limb type
    • AER dependent on PZ to continue developing
overall conclusions aer pz
Overall conclusions: AER, PZ
  • AER required for distal limb development
  • AER keeps PZ in a proliferative state, and PZ sustains AER (feedback loop)
  • What molecules are involved in this interaction??
fgfs and the aer
FGFs and the AER
  • FGFs, including FGF10, FGF8
    • Important in formation, sustaining the AER
  • FGF10 expression in the mesenchyme of the forming limb bud induces formation of AER in the overlying ectoderm
    • This occurs at the distal tip of the limb
    • FGF10 induces expression of FGF8 in AER
    • FGF8 is secreted from AER, signals to PZ to keep dividing
    • FGF8 acts in feedback loop to instruct PZ to maintain FGF10 expression
fgfs and the aer1
FGFs and The AER
  • If the AER is removed from the developing limb
    • Normally, development of distal limb ceases
    • BUT - if remove AER and put in a bead coated in FGF
      • NORMAL DEVELOPMENT OF LIMB!
how are cells specified with regard to p d axis
How are cells specified with regard to P-D axis?
  • The AER and PZ allow for limb outgrowth, but how do proximal cells know to form humerus, distal cells know to form digits?
  • 2 Models
    • Progress zone model
    • Early allocation and progenitor expansion model
p d axis specification guess who
P-D axis specification: Guess who?
  • Regardless of which model for the P-D axis wins out . . .
  • Hox genes appear to be involved!
    • These genes are expressed in a nested pattern that changes during limb development
    • When mutations occur, changes can occur in the P-D axis
slide21
A= Wild Type Mouse; B = Hox a-11, Hox d11 double mutant mouse; C = Human Polysyndactyly (HomozygousHoxD13 mutation)
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