Figure 1: The figure shows the formation, elongation and segmentation of the digits in the mouse forelimb. Left panel: whole-mount in-situ hybridization with probes showing precartilaginous condensations (Sox9), cartilage condensations (Col2a1) and joint interzones (Gdf5). Right panel: skeletal preparation of a newborn mouse hand. Digits 1-5 are indicated, m=metacarpal, p1-p3=phalanges 1-3. From Stricker and Mundlos, Developmental Dynamics 2011, 240(5), 990-1004.
To elucidate the genetic mechanisms of digit formation and elongation we analyze a group of human hand malformations, the brachydactylies (Greek, brachys=short, dactylos=finger) as well as other inheritable conditions. The identification of disease-causing mutations in these syndromes provided a wealth of information, which is further analyzed in different experimental setups. We are mainly interested in analyzing the pathomechanism that leads to malformation using animal models.
Genetics of Digit Elongation
In our analysis we focus on the most severe form of the brachydactylies, brachydactyly type B1. BDB1 is characterized by shortening/hypoplasia/aplasia of the distal phalanges, is caused by mutations in ROR2, encoding a receptor tyrosine kinase. BDB mutations in ROR2 truncate the protein either immediately in front of or after the tyrosine kinase domain leading to the expression of truncated proteins. In contrast, missense or nonsense mutations leading to amino acid exchange or truncation of extracellular domains of ROR2, truncation within the TK domain, or selective inactivation of TK activity lead to autosomal recessive Robinow syndrome (RRS).