The development of postaxial polydactyl is a result of genetic defects in genes that are crucial for the patterning of the three-dimensional axis of the developing limb, particularly the anterior-posterior axis 20. The genetic defects can be caused by mutations in specific genes of chromosomes or in cis-regulatory elements responsible for the expression of genes that are key in the patterning of the anterior-posterior axis of the developing limb bud. As discussed earlier, the ZPA which is located on the lateral plate mesoderm, produces a SHH gradient that is crucial for defining the digits of the limb bud as the level of SHH expression dictates the digit that will be produced as shown in figure 3. Therefore, it is likely that postaxial polydactyly is a result of mutations affecting the expression of SHH.
Specifically, a mutation of the SHH gene resulting in the disruption of the SHH-controlled process of regulating its downstream targets or even a direct mutation of GLI3 itself can be attributed with causing postaxial polydactyly 21. The signalling molecule SHH is a diffusible molecule which binds to the transmembrane protein, patched (Ptc) preventing its inhibitory function of another transmembrane protein, smoothened (Smo). Smo is then able to inhibit the proteolysis of the transcription factor, cubitus interruptus (ci) and uncleaved ci enters the nucleus acting as gene activators to directly activate transcription of SHH genes such as Grem-1 which antagonizes GLI3 22. Grem-1 and the GLI3 gene each belong to a family of genes involved in the normal patterning of the digits by producing proteins to attach to specific regions of DNA controlling gene expression with the latter repressing posterior limb genes. Grem-1 antagonizes GLI3, ensuring GLI3 activity is confined to the anterior part of the limb bud 23. SHH expression is most concentrated closer to its origin, the ZPA, therefore GLI3 is repressed at the posterior of the limb bud allowing for posterior structures to form thus defining the ulnar side of the hand and the first digit (little finger). As the concentration and exposure of SHH to cells decreases anteriorly less GLI3 is repressed defining the anterior aspect and the subsequent digits becoming the radial side of the hand 24.
Fundamentally the digits 3,4 and 5 are specified by a gradient of SHH while digit 2 is specified by long-ranged SHH and digit 1 does not require SHH as shown in figure 3. After being defined the digits are produced via the release of BMPs (BMP-2) which are growth factors that are released during limb bud development, inducing chondrogenesis, the condensation of mesenchymal cells. During chondrogenesis, mesenchymal condensations produce cartilage, forming the skeletal primordia. This cartilage skeleton is replaced by bones to form the digit. Grem-1 by inhibiting BMPs ensures that the digits are correctly defined producing the interdigital space of the digits via apoptosis 25.
a mutation of the SHH gene and its effect on GLI3 would disrupt the formation of the digits for the developing limb bud and produce postaxial polydactyly. When there is a mutation of SHH, the SHH gradient will be disrupted resulting in a shift of the SHH dependent targets. Due to this shift, Grem-1 would antagonize GLI3 earlier than normal resulting in GLI3 not being able to correctly repress posterior structures in the anterior region of the developing limb bud. This would result in the formation of posterior structures coming to a halt slower than normal and due to the increase of SHH, Grem-1 will be able to take effect earlier and more posteriorly in the anterior-posterior axis. Grem-1 will inhibit BMP-2 earlier which induces mesenchymal cells to either become cartilage-producing chondrocytes or undergo apoptosis earlier allowing for the first digit to be formed earlier than usual 26. The disruption of the SHH gradient also results in a longer period taken for the targets of SHH to reach a low enough threshold to provide the identity of the final digit (the thumb) as shown in figure 3. This extended developmental period and lack of GLI3 to repress posterior structures allows for the formation of an extra digit on the posterior of anterior-posterior axis, which becomes the ulnar side of the hand, resulting in postaxial polydactyl.