. Several craniofacial syndromes (Apert, Cruzon, Pfeiffer, Muenke) are due to stenosis, or premature fusion of the bones of the skull. Strikingly, all are caused by mutations in components of the Fgf signaling pathway, and are also associated with hand and foot defects—most commonly syndactyly (see image).
Interestingly (and perhaps incidentally), work in bat embryos has implicated sustained Fgf signaling in the development of bat wings compared to bat hind limbs or compared to mouse limbs (see image). In bat limb development, the forelimbs show elongation of the digits and retention of interdigit soft tissues. Based on this model, would you anticipate that the Fgf mutations seen in craniofacial syndromes reflect a gain of function or loss of function in the Fgf signaling pathway and why?
The connection between limb defects and craniofacial defects is not well understood. However, several studies suggest that the mutations seen in Apert syndrome as well as Pfeiffer and Muenke syndromes result in either enhanced affinity of the Fgf-receptor for its normal ligands or a loss of specificity (resulting in the receptor binding multiple ligands), both of which would enhance Fgf signaling. While cross-species comparisons are not always valid, these observations are consistent with the observed increased Fgf expression in the interdigit regions of bat forelimbs, which results in the retention of interdigit tissues and increased cell proliferation. How enhanced Fgf signaling results in stenosis is not clear, but increased proliferation and decreased cell death would be consistent with premature expansion/fusion of the bones of the skull.