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LIMBS

     The fossil record indicates that tetrapod limbs evolved from the fins of sarcopterygian fish. 

     Eusthenopteron has the same basic organization of bones in its fins as tetrapods had in their limbs with the exception of lacking a wrist, ankle, hand and foot.  There were a number of cartilaginous fin rays in the general area that would later compose the tetrapod hands and feet.

FIN OF EUSTHENOPTERON FIN OF EUSTHENOPTERON
FIN OF EUSTHENOPTERON

In tetrapod embryos, the arm and leg begin their development as paddle-like structures.

Chick

LIMB BUD IN CHICK LIMB BUD IN CHICK
DEVELOPING LIMB IN PIG EMBRYO
DEVELOPING LIMB IN PIG EMBRYO DEVELOPING LIMB IN PIG EMBRYO
DEVELOPING LIMB IN PIG EMBRYO DEVELOPING LIMB IN PIG EMBRYO
DEVELOPING LIMB IN PIG EMBRYO DEVELOPING LIMB IN PIG EMBRYO
DEVELOPING LIMB IN PIG EMBRYO DEVELOPING LIMB IN PIG EMBRYO
DEVELOPING LIMB IN PIG EMBRYO DEVELOPING LIMB IN PIG EMBRYO
DEVELOPING LIMB IN PIG EMBRYO

     Limb buds possess three important signaling centers: the apical ectodermal ridge (AER) which produces FGFs, the zone of polarizing activity (ZPA) which produces Shh, and the nonridge ectoderm. FGFs and Shh control Hox expression (Sanz-Ezquerro, 2003).  In the limb bud, the apical epidermal ridge induces high rates of cell division in the progress zone.  The anterior-posterior differentiation of the limb is controlled by the zone of polarizing activity (ZPA).  Apoptosis occurs between the radius and ulna and between digits to form separated structures (Manouvrier-Hanu, 1999).  The growth factors FGF10, 8, 2 and 4 have important roles in limb development such as the induction of the AER and ZPA (neither of which form in FGF10 mutants) and in the initiation and maintenance of SHH signaling. (Manouvrier-Hanu, 1999)

     SHH is secreted from the posterior region ZPA (and is repressed anteriorly by aristaless-like4) and helps to determine the anterior-posterior polarity.  IHH functions in cartilage development and mutations can cause polydactyly (Manouvrier-Hanu, 1999).

Three zinc finger proteins (GLI1-3) are involved in the Hedgehog signaling pathway and are homologs of the segment polarity gene cubitus interruptus.  Interruptions in this pathway can cause polydactyly with up to 8 digits.  (This is interesting since the earliest known tetrapods possessed polydactyl hands and feet with up to eight digits).  Shh, FGF4, and HoxD13 function at the anterior margin of the limb bud.  Interrupting Formin regulation of Shh can cause the absence of a thumb, fusion of 3rd and 4th digits, and radio-ulnar syntosis.  Mutations in FGF receptor proteins 2 and 3 can cause syndactyly of hands and feet; brachdactyly, finger-like thumbs, triphalangeal thumbs, fusion of ankle and wrist, and tibial curvature, among other changes (Manouvrier-Hanu, 1999).

     TBX mutations can cause the absence or duplication of fifth finger among other changes.  The TGFβ family includes BMPs and cartilage-derived morphogenetic protein (CDMP).  Smad proteins (MAD homolog) mediate these signals affect on the nucleus.  BMPs are the vertebrate homologs of decapentaplegic genes (Manouvrier-Hanu, 1999).  In all coelomate animals, HOX clusters are important in providing positional information to cells along an axis.  In tetrapods, HOX clusters not only generate an axis along the length of the body, in the brain, and in the digestive system, they do so in the limbs as well.  In humans and other vertebrates, HOXD13 and HOXA13 are important for distal part of limb.  HOXD9 is expressed in a more proximal region of the limb (Manouvrier-Hanu, 1999).

HUMAN FOOT
One in about one thousand human births suffers a limb anomaly.  Limb abornmalities include extra digits, extra carpals, fused carpals, extra phalanges, and the loss of metacarpals, proximal and middle phalanges.
LIMB ABNORMALITIES