Distinct function of P63 isoforms during embryonic skeletal development.
Distinct function of P63 isoforms during embryonic skeletal development.
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DOI：
10.1016/j.gene.2013.02.021
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发表时间：
2013-05-01
期刊：
影响因子：
3.5
通讯作者：
Zheng Q
中科院分区：
文献类型：
--
作者：
Lu Y;Abbassi S;Li F;Ding M;Wu G;Gu J;Zheng Q
P63属于转录因子P53家族。有多种P63亚型在癌症和发育中发挥重要作用。p63基因敲除小鼠和P63基因突变的人类骨骼综合征中明显的肢体缺陷表明其在长骨发育中的重要作用。然而，不同的P63亚型如何在长骨发育过程中发挥作用在很大程度上是未知的。我们之前已经证明，最长的P63亚型TAP 63 α在胚胎骨骼发育中起着积极的作用，因为靶向TAP 63 α在肥大软骨细胞中的表达加速了E17.5和P1阶段的软骨内骨化。在这里，我们报告了Δ NP 63 α的转基因研究，Δ NP 63 α是另一种P63亚型，与TAP 63 α相比缺乏N-末端反式激活结构域，使用相同的肥大软骨细胞特异性Col 10a 1控制元件。在这些Col 10a 1-Δ NP 63 α转基因小鼠中，在E17.5和P1阶段均未检测到骨骼异常，表明Δ NP 63 α在晚期胚胎骨骼发育中的重要性较小。为了进一步研究P63亚型在早期骨骼发育中的功能，我们使用软骨细胞特异性Col 2a 1对照元件产生了Δ NP 63 α和TAP 63 α转基因小鼠。令人惊讶的是，虽然在Col 2a 1-Δ NP 63 α转基因小鼠中没有显示骨骼缺陷，但与其野生型同窝小鼠相比，在E17.5和P1阶段的Col 2a 1-TAP 63 α转基因小鼠的趾和尾骨中观察到骨化减少。表达谱和免疫组化分析检测到Sox 9在Col 2a 1-TAP 63 α转基因小鼠中的表达上调，Sox 9是软骨内骨化的主要负调节因子。综上所述，我们的研究结果表明，在软骨内骨化过程中，P63亚型，在这里，Δ NP 63 α和TAP 63 α，具有不同的功能。
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.
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