Hoxa11 and Hoxd11 loss-of-function mutations alter pisiform growth plate organization

Mammalian pisiforms are typically elongated and develop from two centers of ossification with a single organized growth plate on the palmar end; however human pisiforms are unique among mammals because they are short, develop from a single ossification center, and lack a growth plate. Hox genes provide crucial developmental patterning information, and are thought to influence growth plate formation. Hoxa11 and Hoxd11 are expressed around the developing pisiform in mice, and mutations to these genes result in abnormal shortening of the pisiform. This study seeks to determine if Hoxa11 and Hoxd11 loss-of-function mutations influence pisiform growth plate formation and chondrocyte organization, resulting in the observed pisiform shortening compared to wild type. Histological analyses of Hoxa11 and Hoxd11 mutant mouse pisiforms indicate that abnormal chondrocyte rganization occurs in heterozygotes and homozygotes for either deletion. Severity of organizational abnormalities is dosage dependent for both genes. Hoxa11 mutants lack a distinct hypertrophic zone and exhibit a reduced columnar zone. All chondrocytic zones appear reduced in Hoxd11 heterozygotes, with more marked disorganization in homozygotes. Hoxd11 mutants also have irregular progression of the ossification front. These results support the role of Hox genes in pisiform growth plate formation and overall pisiform length in Hoxa11 and Hoxd11 mutant mice. Understanding the influence of Hox genes on chondrocyte organization may also help to explain developmental processes responsible for growth plate loss in the unique human pisiform. This research is funded by the Hill Fellowship (Department of Anthropology, Penn State) and NSF BCS-1540418.