Distinct function of P63 isoforms during embryonic skeletal development.

ABSTRACT: P63 belongs to the P53 family of transcription factors. There are multiple P63 isoforms that play important functions both in cancer and development. The obvious limb defect in p63 null mice and in human skeletal syndromes with P63 mutations suggest its essential role in long bone development. However, how the different P63 isoforms function during long bone development is largely unknown. We have previously shown that TAP63?, the longest P63 isoform, plays a positive role in embryonic skeletal development, since targeting TAP63? expression in hypertrophic chondrocytes accelerates endochondral ossification at both E17.5 and P1 stages. Here, we report transgenic studies of ?NP63?, another P63 isoform which lacks the N-terminal transactivation domain compared to TAP63?, using the same hypertrophic chondrocyte-specific Col10a1 control element. No skeletal abnormalities were detected in these Col10a1-?NP63? transgenic mice at both E17.5 and P1 stages, suggesting less importance of ?NP63? during late embryonic skeletal development. To further investigate the function of P63 isoforms during early skeletal development, we have generated ?NP63? and TAP63? transgenic mice using a chondrocyte-specific Col2a1 control element. Surprisingly, while no skeletal defect was shown in the Col2a1-?NP63? transgenic mice, reduced ossification was observed in the digit and tail bones of Col2a1-TAP63? transgenic mice at both E17.5 and P1 stages compared to their wild-type littermates. Expression profiling and immunohistochemical analysis detected upregulated expression of Sox9, a major negative regulator of endochondral ossification, in Col2a1-TAP63? transgenic mice. Taken together, our results suggest a distinct function of P63 isoforms, herein, ?NP63? and TAP63?, during endochondral ossification.

SUBMITTER: Lu Y 

PROVIDER: S-EPMC3628837 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature