Limb patterning proximal distal axis
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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

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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

      • Dorsal/ventral

      • Anterior/Posterior

      • Proximal/distal


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


John Saunders


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


PZ


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


Removal of AER at different times: loss of various structures


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

  • 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, 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


FGF8 expression


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?

  • 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?

  • 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


Specific Hox Paralog groups are expressed in specific regions of the limb


A= Wild Type Mouse; B = Hox a-11, Hox d11 double mutant mouse; C = Human Polysyndactyly (HomozygousHoxD13 mutation)


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