参与初级纤毛分解的相关基因Pitchfork通过Shh信号通路调控小鼠腭部发育的作用机制

Mammalian palate development is regulated by complex processes. Many cellular and molecular events, such as cell proliferation, apoptosis, cell migration and the epithelial mesenchymal transition, regulate proper palate development, and surely, some abnormalities in palate development lead to cleft palate. Various developmental disorders, such as cleft palate, and disorders of the lung, kidney and heart, have been known as an association with ciliary defects. Pitchfork, a mouse embryonic node gene, is associated with ciliary targeting complexes located at the basal body during primary cilia disassembly. To determine the function of Pitchfork during palate development, we examined Pitchfork expression patterns and morphological changes in the developing secondary palate after Pitchfork over-expression. During periods E12.5 and E13.5 in mice, Pitchfork was highly expressed in the developing mouse secondary palate. Morphological differences were observed in vitro in cultured palates in the Pitchfork over-expression group compared to the control group. Pitchfork over-expression induced primary cilia disassembly during mouse palate development. Shh and Ptch1 expression levels and palatine rugae morphology were altered in the over-expressed Pitchfork group during palate development. In this study, we clarified the mechanism of primary cilia-related gene Pitchfork and Shh signaling pathway, provided new ideas for prevention and treatment of palate developmental disorders.

哺乳类动物的腭部发育是许多种细胞和分子机制参与的复杂过程。如细胞增殖，凋亡，细胞迁移，上皮和间充质细胞相互转换，对腭部正常发育起重要调控作用，反之这些调控失调，会导致腭裂。许多器官的发育异常，如腭裂以及肺，肾脏，心脏等，已被认为与初级纤毛缺陷有关。Pitchfork（Pifo）是小鼠胚胎节点基因，位于初级纤毛的基粒底部，参与初级纤毛的分解过程。为了证明Pifo在腭部发育中的作用，我们检测了Pifo在小鼠继发腭发育中的表达模式和Pifo过表达后的形态学改变。在胚胎周期12.5和13.5时，Pifo在继发腭间充质细胞中有较强的表达。体外培养小鼠继发腭，发现Pifo过表达组与对照组之间有明显形态学差异。Pifo过表达会诱导初级纤毛分解，还改变Shh和Ptch1的表达量及腭皱褶的形态。本研究通过阐明初级纤毛相关基因Pifo与Shh信号通路的作用机制，为腭部发育的相关性疾病的预防、治疗提供新的思路。

在颌面部形态发育中，腭部发育及其重要。初级纤毛在许多组织和器官的发育成形过程中起重要作用，同时也决定了其结构和功能的异常导致多种纤毛相关疾病的发生，包括腭裂以及肺，肾脏，心脏等器官的发育异常。初级纤毛是一种非运动性信号作用细胞器，它存在于几乎所有哺乳动物细胞类，基粒、轴纤丝、纤毛质膜是初级纤毛的重要组成部分。其中基粒是纤毛发生的核心，调节从细胞质到纤毛质膜的运输作用。Pitchfork是小鼠胚胎节点基因，位于初级纤毛的基粒底部， 在许多组织、器官发育中，Pitchfork 参与早期初级纤毛的合成和分解，从而使之平衡。另外，我们还研究了奥皮茨综合征相关基因Midline1与腭裂的关系。本研究通过阐明Pitchfork、Midline1基因在小鼠腭部发育过程中的重要作用机制，为腭部发育的相关性疾病的预防、治疗提供新的思路。