title: 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 TAP63α, the longest P63 isoform, plays a positive role in embryonic skeletal development, since targeting TAP63α expression in hypertrophic chondrocytes accelerates endochondral ossification at both E17.5 and P1 stages. Here, we report transgenic studies of ΔNP63α, another P63 isoform which lacks the N-terminal transactivation domain compared to TAP63α, using the same hypertrophic chondrocyte-specific Col10a1 control element. No skeletal abnormalities were detected in these Col10a1-ΔNP63α transgenic mice at both E17.5 and P1 stages, suggesting less importance of ΔNP63α during late embryonic skeletal development. To further investigate the function of P63 isoforms during early skeletal development, we have generated ΔNP63α and TAP63α transgenic mice using a chondrocyte-specific Col2a1 control element. Surprisingly, while no skeletal defect was shown in the Col2a1-ΔNP63α transgenic mice, reduced ossification was observed in the digit and tail bones of Col2a1-TAP63α 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-TAP63α transgenic mice. Taken together, our results suggest a distinct function of P63 isoforms, herein, ΔNP63α and TAP63α, during endochondral ossification.
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Yaojuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Sam
authors.initials: S
authors.lastname: Abbassi
authors.forename: Feifei
authors.initials: F
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Ding
authors.forename: Guojun
authors.initials: G
authors.lastname: Wu
authors.forename: Junxia
authors.initials: J
authors.lastname: Gu
authors.forename: Qiping
authors.initials: Q
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000196:embryology* / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D003001:Cloning, Molecular; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C570620:Col10a1 protein, mouse; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D024121:Collagen Type X; D005819:Genetic Markers; D010750:Phosphoproteins; D020033:Protein Isoforms; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D015534:Trans-Activators; C486419:Trp63 protein, mouse