Hoxa11 and Hoxd11 influence pisiform length through altered growth plate organization

Mammalian pisiforms are typically elongated, form from two centers of ossification, and contain an organized growth plate at the palmar end; however, human pisiforms are short, have lost an ossification center, and lack a growth plate. Orangutans also have shortened pisiforms, but retain two ossification centers. In mice, Hoxa11 and Hoxd11 are expressed around the developing pisiform, and mutations to these genes produce abnormally short pisiforms. This study uses histological analyses to examine the structure of developing pisiforms in Hoxa11 and Hoxd11 mutant mice to determine if the growth plate is altered by loss-of-function of either gene. Abnormal pisiform growth plate cartilage organization is observed in both Hoxa11 and Hoxd11 mutants in a dosage-dependent manner. Heterozygotes and homozygotes for the Hoxa11 deletion lack a distinct hypertrophic zone, have a reduced columnar zone, and have shorter pisiforms than wild types. All chondrocytic zones appear reduced in Hoxd11 heterozygotes, and Hoxd11 homozygous mutants have disorganized cartilage where the growth plate typically forms. Hoxd11 mutants also have short pisiforms and an abnormal ossification front, which is less apparent in Hoxa11 mutants. These results support the role of Hox genes in pisiform growth plate formation and overall pisiform length. Human and orangutan pisiform reduction is likely convergent since orangutans retain a secondary ossification center, while humans do not. Given variability in growth plate structure between Hoxa11 and Hoxd11 mutants, these data may also help to explain developmental processes responsible for variation in the piso- triquetral complex in humans and orangutans compared to other hominoids.